Integrin antagonists

ABSTRACT

This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor antagonists. The vitronectin receptor antagonist compounds of the present invention are αvβ3 antagonists, αvβ5 antagonists or dual αvβ3/αvβ5 antagonists useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.

FIELD OF THE INVENTION

The present invention is related to U.S. provisional applications Ser.Nos. 60/047,177, filed May 20, 1997, 60/033,579, filed Dec. 19, 1996,and 60/025,123, filed Aug. 29, 1996, the contents of which are herebyincorporated by reference.

The present invention provides novel compounds and derivatives thereof,their synthesis, and their use as vitronectin receptor ligands. Moreparticularly, the compounds of the present invention are αvβ3antagonists, (αvβ5 antagonists or dual αvβ3/αvβ5 antagonists useful forinhibiting bone resorption, treating and preventing osteoporosis, andinhibiting vascular restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, inflammation and tumorgrowth.

BACKGROUND OF THE INVENTION

This invention relates to compounds for inhibiting bone resorption thatis mediated by the action of a class of cells known as osteoclasts.

Osteoclasts are multinucleated cells of up to 400 μm in diameter thatresorb mineralized tissue, chiefly calcium carbonate and calciumphosphate, in vertebrates. They are actively motile cells that migratealong the surface of bone. They can bind to bone, secrete necessaryacids and proteases and thereby cause the actual resorption ofmineralized tissue from the bone.

More specifically, osteoclasts are believed to exist in at least twophysiological states. In the secretory state, osteoclasts are flat,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruffled border, and secrete lysosomalenzymes and protons to resorb bone. The adhesion of osteoclasts to bonesurfaces is an important initial step in bone resorption. In themigratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they attach again to bone.

Integrins are transmembrane, heterodimeric, glycoproteins which interactwith extracellular matrix and are involved in osteoclast attachment,activation and migration. The most abundant integrin in osteoclasts(rat, chicken, mouse and human) is the vitronectin receptor, or αvβ3,thought to interact in bone with matrix proteins that contain the RGDsequence. Antibodies to αvβ3 block bone resorption in vitro indicatingthat this integrin plays a key role in the resorptive process. There isincreasing evidence to suggest that αvβ3 ligands can be used effectivelyto inhibit osteoclast mediated bone resoption in vivo in mammals.

The current major bone diseases of public concern are osteoporosis,hypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment.

All these conditions are characterized by bone loss, resulting from animbalance between bone resorption (breakdown) and bone formation, whichcontinues throughout life at the rate of about 14% per year on theaverage. However, the rate of bone turnover differs from site to site,for example, it is higher in the trabecular bone of the vertebrae andthe alveolar bone in the jaws than in the cortices of the long bones.The potential for bone loss is directly related to turnover and canamount to over 5% per year in vertebrae immediately following menopause,a condition which leads to increased fracture risk.

There are currently 20 million people with detectable fractures of thevertebrae due to osteoporosis in the United States. In addition, thereare 250,000 hip fractures per year attributed to osteoporosis. Thisclinical situation is associated with a 12% mortality rate within thefirst two years, while 30% of the patients require nursing home careafter the fracture.

Individuals suffering from all the conditions listed above would benefitfrom treatment with agents which inhibit bone resorption.

Additionally, αvβ3 ligands have been found to be useful in treatingand/or inhibiting restenosis (recurrence of stenosis after correctivesurgery on the heart valve), atherosclerosis, diabetic retinopathy,macular degeneration and angiogenesis (formation of new blood vessels).Moreover, it has been postulated that the growth of tumors depends on anadequate blood supply, which in turn is dependent on the growth of newvessels into the tumor; thus, inhibition of angiogenesis can cause tumorregression in animal models. (See, Harrison's Principles of InternalMedicine, 12th ed., 1991). αvβ3 antagonists, which inhibit angiogenesis,are therefore useful in the treatment of cancer for inhibiting tumorgrowth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).

Moreover, compounds of this invention can also inhibitneovascularization by acting as antagonists of the integrin receptorαvβ5. A monoclonal antibody for αvβ5 has been shown to inhibitVEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoicmembrane model; M. C. Friedlander, et.al., Science 270, 1500-1502, 1995.Thus, compounds that antagonize αvβ5 are useful for treating andpreventing macular degeneration, diabetic retinopathy, and tumor growth.

In addition, certain compounds of this invention antagonize both theαvβ3 and αvβ5 receptors. These compounds, referred to as "dual αvβ3/αvβ5antagonists," are useful for inhibiting bone resorption, treating andpreventing osteoporosis, and inhibiting vascular restenosis, diabeticretinopathy, macular degeneration, angiogenesis, atherosclerosis,inflammation and tumor growth.

It is an object of the present invention to identify compounds whichbind to the αvβ3 receptor, αvβ5 receptor or both the αvβ3 and αvβ5receptors.

It is a further object of the invention to identify compounds which actas antagonists of the αvβ3 receptor. It is another object of theinvention to identify αvβ3 antagonist compounds which are useful agentsfor inhibiting: bone resorption mediated by osteoclast cells,restenosis, atherosclerosis, inflammation, diabetic retinopathy, maculardegeneration and angiogenesis in animals, preferably mammals, especiallyhumans. Still another object of the invention is to identify αvβ3antagonists which cause tumor regression and/or inhibit tumor growth inanimals.

A further object of the invention is to identify αvβ3 antagonists usefulfor preventing or treating osteoporosis. An additional object of theinvention is to identify αvβ3 antagonists useful for treating cancer.

It has now been found that the compounds of the present invention, αvβ3ligands, are useful for inhibiting bone resorption in mammals. Thus, thecompounds of the present invention are useful for preventing or reducingthe incidence of osteoporosis. Additionally, the αvβ3 ligands of thepresent invention are also useful for treating and/or inhibitingrestenosis, diabetic retinopathy, macular degeneration, atherosclerosisand/or angiogenesis in mammals.

SUMMARY OF THE INVENTION

The present invention provides a method of eliciting a vitronectinreceptor antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound of the formula ##STR1## wherein X is selected from ##STR2## a5- or 6-membered monocyclic aromatic or nonaromatic ring systemcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S whereinthe 5- or 6-membered ring system is either unsubstituted or substitutedon a carbon or nitrogen atom with one or more groups chosen from R¹, R²,R¹⁵ or R¹⁶ ;

a 9- to 10-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system contains 0, 1,2, 3 or 4 heteroatoms selected from N, O or S, and wherein thepolycyclic ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups chosen from R¹, R², R¹⁵or R¹⁶ ;

Y is selected from ##STR3## Z is a 5-11 membered aromatic or nonaromaticmono- or polycyclic ring system containing 0 to 6 double bonds, andcontaining 0 to 6 heteroatoms chosen from N, O and S, and wherein thering system is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selected from R⁴,R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclic aromaticring system, an isoxazoline ring or an isoxazole ring;

R¹, R², R⁴, R⁵, R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selectedfrom hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino,C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(q) amino, (C₁₋₆ alkyl)_(q)amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonylC₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl,C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q), (C₁₋₈ alkyl)_(q)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(q)aminocarbonyloxy, oxo, (aryl C₁₋₈ alkyl)_(q) amino, (aryl)_(q) amino,aryl C₁₋₈ alkylsulfonylamino or C₁₋₈ alkylsulfonylamino;

R³ is selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

hydroxyl,

C₁₋₅ alkoxy,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(q) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(q) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(q) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(q) aminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, or

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted with

R¹³ and R¹⁴ ;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

aryl-(CH₂)_(n) --O--(CH₂)_(m) --,

aryl-(CH₂)_(n) --S(O)_(q) --(CH₂)_(m) --,

aryl-(CH₂)_(n) --C(O)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --C(O)--N(R³)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --N(R³)--C(O)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --N(R³)--(CH₂)_(m) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

(C₁₋₆ alkyl)_(q) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₅ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, (C₁₋₅ alkyl)_(q)aminocarbonyl, C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, (C₁₋₃alkyl)_(q) amino, amino C₁₋₃ alkyl, (aryl)_(q) aminocarbonyl, (aryl C₁₋₅alkyl)_(q) aminocarbonyl, aminocarbonyl, aminocarbonyl C₁₋₄ alkyl,hydroxycarbonyl or hydroxycarbonyl C₁₋₅ alkyl,

CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

(aryl)_(q) amino,

(aryl)_(q) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(q) amino,

(aryl C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(q) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminocarbonylamino,

(C₁₋₈ alkyl)_(q) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(q) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(q) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminosulfonylamino,

(C₁₋₈ alkyl)_(q) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(q) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(q) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(q) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminocarbonyl, or

(aryl C₁₋₈ alkyl)_(q) aminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, or

C₁₋₈ dialkylaminocarbonylmethylene;

m, s and t are each independently an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6;

and the pharmaceutically acceptable salts thereof.

In one embodiment of the present invention is the method of eliciting avitronectin antagonizing effect wherein

X is

a 9- to 10-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system contains 0, 1,2, 3 or 4 heteroatoms selected from N, O or S, and wherein thepolycyclic ring system is either unsubstituted or substituted on acarbon atom with R¹ and R² ; and

Z is selected from ##STR4## and all other variables are as definedabove; and the pharmaceutically acceptable salts thereof. Preferably, Zis selected from ##STR5##

In a class of the invention is the method of eliciting a vitronectinantagonizing effect wherein the compound has the formula ##STR6##wherein X is selected from ##STR7## Y is selected from --(CH₂)_(r) -- or--(CH₂)_(m) --NR³ --(CH₂)_(t) --;

R³ is selected from

hydrogen,

aryl-(CH₂)_(p) --,

C₁₋₅ alkoxycarbonyl,

C₃₋₈ cycloalkyl,

(aryl)_(q) aminocarbonyl,

(aryl C₁₋₈ alkyl)_(q) aminocarbonyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

C₁₋₆ alkylsulfonyl, or

aryl C₁₋₆ alkylcarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ;

R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl or aryl C₁₋₈ alkyl,

R⁸ is selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; and

r is an integer from 0 to 3;

and all other variables are as defined above;

and the pharmaceutically acceptable salts thereof.

In a subclass of the invention is the method wherein the compound hasthe formula ##STR8## wherein Z is selected from ##STR9## R⁸ is selectedfrom hydrogen, ##STR10## indolyl-(CH₂)_(p) --, CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; and

R¹² is selected from hydrogen or C₁₋₈ alkyl;

s is an integer from 0 to 3;

and all other variables are as defined above;

and the pharmaceutically acceptable salts thereof.

Illustrative of the invention is the method of eliciting a vitronectinantagonizing effect wherein the compound is selected from

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alaninetrifluoroacetate;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine;

Ethyl3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS,6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR,6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3(S)-pyridin-3-yl-propionicacid;

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester;

2-Oxo-5(R)-methyl-3(S)-[2-(5 ,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid ethyl ester; or

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid;

3-{2-(2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)-acetylamino}-3(S)-quinolin-3-yl-propionicacid;

3-(2-(5(S)-Ethyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrolidin-1-yl)-acetylamino)-3-(S)-quinolin-3-yl-propionicacid trifluoroacetate;

3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid bis trifluoroacetate; or

3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]napthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid ethyl ester;

and the pharmaceutically acceptable salts thereof.

Preferably, the compound is selected from

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alaninetrifluoroacetate;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine;

3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS,6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR,6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid;

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;or

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid;

and the pharmaceutically acceptable salts thereof.

Exemplifying the invention is the method wherein the vitronectinreceptor antagonizing effect is an αvβ3 antagonizing effect. Anillustration of the invention is the method wherein the αvβ3antagonizing effect is selected from inhibition of: bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation or tumor growth. Preferably, the αvβ3 antagonizing effectis the inhibition of bone resorption.

An example of the invention is the method wherein the vitronectinreceptor antagonizing effect is an αvβ5 antagonizing effect. Morespecifically, the αvβ5 antagonizing effect is selected from inhibitionof: restenosis, angiogenesis, diabetic retinopathy, maculardegeneration, inflammation or tumor growth.

Illustrating the invention is the method wherein the vitronectinreceptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect.More particularly, the dual αvβ3/αvβ5 antagonizing effect is selectedfrom inhibition of: bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation or tumor growth.

In a second embodiment of the present invention is a method of elicitingan αvβ3 antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound of the formula ##STR11## wherein X is selected from ##STR12## a5- or 6-membered monocyclic aromatic or nonaromatic ring systemcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S whereinthe 5- or 6-membered ring system is either unsubstituted or substitutedon a carbon atom with R¹ and R², or

a 9- to 10-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system contains 0, 1,2, 3 or 4 heteroatoms selected from N, O or S, and wherein thepolycyclic ring system is either unsubstituted or substituted on acarbon atom with R¹ and R² ;

Y is selected from ##STR13## Z is a 5-11 membered aromatic ornonaromatic mono- or polycyclic ring system containing 0 to 6 doublebonds, and containing 0 to 6 heteroatoms chosen from N, O and S, andwherein the ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups independently selectedfrom R⁴, R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclicaromatic ring system; preferably, Z is selected from ##STR14## R¹, R²,R⁴, R⁵, R¹³ and R¹⁴ are each independently selected from hydrogen,halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino,amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆alkylamino, C₁₋₆ alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy orhydroxy C₁₋₆ alkyl;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₁₋₈ alkylaminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

amino,

C₁₋₆ alkylamino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₅ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, C₁₋₅ alkylaminocarbonyl,C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, amino, C₁₋₃ alkylamino,amino C₁₋₃ alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl,aminocarbonyl, aminocarbonyl C₁₋₄ alkyl, hydroxycarbonyl, orhydroxycarbonyl C₁₋₅ alkyl,

--(CH₂)_(s) C.tbd.CH,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkyl,

--(CH₂)_(s) C.tbd.C--C₃₋₇ cycloalkyl,

--(CH₂)_(s) C.tbd.C-aryl,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkylaryl,

--(CH₂)_(s) CH═CH₂,

--(CH₂)_(s) CH═CH C₁₋₆ alkyl,

--(CH₂)_(s) CH═CH--C₃₋₇ cycloalkyl,

--(CH₂)_(s) CH═CH aryl,

--(CH₂)_(s) CH═CH C₁₋₆ alkylaryl,

--(CH₂)_(s) SO₂ C₁₋₆ alkyl,

--(CH₂)_(s) SO₂ C₁₋₆ alkylaryl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

arylamino,

arylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

C₁₋₆ dialkylamino,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₆ alkylaminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonylamino,

C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonylamino,

aryl C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminosulfonylamino,

C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

arylaminosulfonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

arylaminocarbonyl C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonyl, or

aryl C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

hydroxy,

C₁₋₈ alkoxy,

aryloxy,

aryl C₁₋₆ alkoxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

C₁₋₈ alkylaminocarbonylmethyleneoxy, or

C₁₋₈ dialkylaminocarbonylmethyleneoxy;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6;

s is an integer from 0 to 3; and

t is an integer from 0 to 3;

and the pharmaceutically acceptable salts thereof.

In a third embodiment of the invention is a method of eliciting an αvβ3antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound of the formula ##STR15## wherein X is selected from ##STR16## a5- or 6-membered monocyclic aromatic or nonaromatic ring systemcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S whereinthe 5- or 6-membered ring system is either unsubstituted or substitutedon a carbon atom with R¹ and R², or

a 9- to 10-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system contains 0, 1,2, 3 or 4 heteroatoms selected from N, O or S, and wherein thepolycyclic ring system is either unsubstituted or substituted on acarbon atom with R¹ and R² ;

Y is selected from ##STR17## Z is a 5-11 membered aromatic ornonaromatic mono- or polycyclic ring system containing 0 to 6 doublebonds, and containing 0 to 6 heteroatoms chosen from N, O and S, andwherein the ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups independently selectedfrom R⁴, R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclicaromatic ring system; preferably Z is selected from ##STR18## R¹, R²,R⁴, R⁵, R¹³ and R¹⁴ are each independently selected from hydrogen,halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino,amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆alkylamino, C₁₋₆ alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy,hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q),C₁₋₈ aminocarbonyl, C₁₋₈ dialkylaminocarbonyl, C₁₋₈alkyloxycarbonylamino, C₁₋₈ alkylaminocarbonyloxy or C₁₋₈galkylsulfonylamino;

R³ is selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

hydroxyl,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₈ alkylaminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

arylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, or

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₁₋₈ alkylaminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

amino,

C₁₋₆ alkylamino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₅ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, C₁₋₅ alkylaminocarbonyl,C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, amino, C₁₋₃ alkylamino,amino C₁₋₃ alkyl, arylammnocarbonyl, aryl C₁₋₅ alkylaminocarbonyl,aminocarbonyl, aminocarbonyl C₁₋₄ alkyl, hydroxycarbonyl, orhydroxycarbonyl C₁₋₅ alkyl,

--(CH₂)_(s) C.tbd.CH,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkyl,

--(CH₂)_(s) C.tbd.C--C₃₋₇ cycloalkyl,

--(CH₂)_(s) C.tbd.C-aryl,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkylaryl,

--(CH₂)_(s) CH═CH₂,

--(CH₂)_(s) CH═CH C₁₋₆ alkyl,

--(CH₂)_(s) CH═CH--C₃₋₇ cycloalkyl,

--(CH₂)_(s) CH═CH aryl,

--(CH₂)_(s) CH═CH C₁₋₆ alkylaryl,

--(CH₂)_(s) SO₂ C₁₋₆ alkyl,

--(CH₂)_(s) SO₂ C₁₋₆ alkylaryl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

arylamino,

arylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

C₁₋₆ dialkylamino,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₆ alkylaminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonylamino,

C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonylamino,

aryl C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminosulfonylamino,

C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

arylaminosulfonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C1-6 alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋ 6 alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

arylaminocarbonyl C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonyl, or

aryl C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

hydroxy,

C₁₋₈ alkoxy,

aryloxy,

aryl C₁₋₆ alkoxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

C₁₋₈ alkylaminocarbonylmethyleneoxy, or

C₁₋₈ dialkylaminocarbonylmethyleneoxy;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6; and

s is an integer from 0 to 3;

and the pharmaceutically acceptable salts thereof.

Illustrating the invention is the method wherein the αvβ3 antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, inflammation or inhibition of tumor growth. Preferably,the αvβ3 antagonizing effect is the inhibition of bone resorption.

An illustration of the invention is a compound of the formula ##STR19##wherein X is a 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ring systemcontains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, andwherein the polycyclic ring system is either unsubstituted orsubstituted on a carbon or nitrogen atom with one or more groups chosenfrom R¹, R², R¹⁵ or R¹⁶ ;

Y is selected from ##STR20## Z is a 5-11 membered aromatic ornonaromatic mono- or polycyclic ring system containing 0 to 6 doublebonds, and containing 0 to 6 heteroatoms chosen from N, O and S, andwherein the ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups independently selectedfrom R⁴, R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclicaromatic ring system, an isoxazoline ring or an isoxazole ring;

R¹, R², R⁴, R⁵, R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selectedfrom hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino,C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(q) amino, (C₁₋₆ alkyl)_(q)amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonylC₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl,C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q), (C₁₋₈ alkyl)_(q)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(q)aminocarbonyloxy, oxo, (aryl C₁₋₈ alkyl)_(q) amino, (aryl)_(q) amino,aryl C₁₋₈ alkylslfonylamino or C₁₋₈ alkylsulfonylamino;

R³ is selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

hydroxyl,

C₁₋₅ alkoxy,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(q) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(q) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(q) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(q) aminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, or

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

aryl-(CH₂)_(n) --O--(CH₂)_(m) --,

aryl-(CH₂)_(n) --S(O)_(q) --(CH₂)_(m) --,

aryl-(CH₂)_(n) --C(O)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --C(O)--N(R³)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --N(R³)--C(O)--(CH₂)_(m) --,

aryl-(CH₂)_(n) --N(R³)--(CH₂)_(m) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

(C₁₋₆ alkyl)_(q) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₅ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, (C₁₋₅ alkyl)_(q)aminocarbonyl, C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, (C₁₋₃alkyl)_(q) amino, amino C₁₋₃ alkyl, (aryl)_(q) aminocarbonyl, (aryl C₁₋₅alkyl)_(q) aminocarbonyl, aminocarbonyl, aminocarbonyl C₁₋₄ alkyl,hydroxycarbonyl or hyydroxycarbonyl C₁₋₅ alkyl,

CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

(aryl)_(q) amino,

(aryl)_(q) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(q) amino,

(aryl C₁₋₆ alkyl)_(q) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(q) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminocarbonylamino,

(C₁₋₈ alkyl)_(q) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(q) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(q) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminosulfonylamino,

(C₁ -8 alkyl)_(q) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(q) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(q) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(q) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(q) aminocarbonyl, or

(aryl C₁₋₈ alkyl)_(q) aminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, or

C₁₋₈ dialkylaminocarbonylmethylene;

m, s and t are each independently an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6;

and the pharmaceutically acceptable salts thereof.

Particularly illustrative of the invention is the cohmpound wherein Z isa 5-11 membered nonaromatic mono- or polycyclic ring system containing 0to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, Oand S, and wherein the ring system is either unsubstituted orsubstituted on a carbon or nitrogen atom with one or more groupsindependently selected from R⁴, R⁵, R⁶ and R⁷ ; and all other variablesare as defined above.

Exemplifying the invention is the compound wherein Z is selected from##STR21## and the pharmaceutically acceptable salts thereof. PreferablyZ is selected from ##STR22##

An example of the invention is the compound of the formula ##STR23##wherein X is selected from ##STR24## Y is selected from --(CH₂)_(r) --or --(CH₂)_(m) --NR³ --(CH₂)_(t) --;

R³ is selected from

hydrogen,

aryl-(CH₂)_(p) --,

C₁₋₅ alkoxycarbonyl,

C₃₋₈ cycloalkyl,

(aryl)_(q) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(q) aminocarbonyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(q) aminocarbonyl,

C₁₋₆ alkylsulfonyl, or

aryl C₁₋₆ alkylcarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ;

R⁴ is selected from

hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,

C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl,

aryl or aryl C₁₋₈ alkyl,

R⁸ is selected from

hydrogen,

aryl,

aryl-(CH₂)_(p) --,

CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; and

r is an integer from 0 to 3;

wherein all other variables are as defined above;

and the pharmaceutically acceptable salts thereof.

Further illustrating the invention is the compound of the formula##STR25## wherein Z is selected from ##STR26## R⁸ is selected fromhydrogen, ##STR27## indolyl-(CH₂)_(p) --, CH.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --,

aryl-C.tbd.C--(CH₂)_(s) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --,

CH₂ ═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --,

aryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; and

R¹² is selected from hydrogen or C₁₋₈ alkyl; and s is an integer from 0to 3; and all other variables are as defined above; and thepharmaceutically acceptable salts thereof.

Further exemplifying the invention is the compound selected from

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alaninetrifluoroacetate;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanineethyl ester;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanineethyl ester;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine;

Ethyl2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylinddol-3-yl)-β-alanine;

Ethyl3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS,6aS)_(p)yrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR,6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid;

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanineethyl ester;

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanineethyl ester;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}acetylamino)-propionicacid ethyl ester; or

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid;

and the pharmaceutically acceptable salts thereof.

Preferably, the compound is selected from

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alaninetrifluoroacetate;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine;

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-tetrahydropyrimidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine;

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine;

3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid;

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS,6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionicacid; or

3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR,6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino-}-3-(S)-pyridin-3-yl-propionicacid;

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine;

5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine;or

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid;

and the pharmaceutically acceptable salts thereof.

An additional example of the invention is a compound of the formula##STR28## wherein X is a 9- to 10-membered polycyclic ring system,wherein one or more of the rings is aromatic, and wherein the polycyclicring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstituted orsubstituted on a carbon atom with R¹ and R² ;

Y is selected from ##STR29## Z is a 5-11 membered aromatic ornonaromatic mono- or polycyclic ring system containing 0 to 6 doublebonds, and containing 0 to 6 heteroatoms chosen from N, O and S, andwherein the ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups independently selectedfrom R⁴, R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclicaromatic ring system; preferably, Z is selected from ##STR30## R¹, R²,R³, R⁴, R⁵, R¹³ and R¹⁴ are each independently selected from hydrogen,halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino,amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆alkylamino, C₁₋₆ alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy orhydroxy C₁₋₆ alkyl;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₁₋₈ alkylaminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

amino,

C₁₋₆ alkylamino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₈ 5 alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, C₁₋₅ alkylaminocarbonyl,C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, amino, C₁₋₃ alkylamino,amino C₁₋₃ alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl,aminocarbonyl, aminocarbonyl C₁₋₄ alkyl, hydroxycarbonyl, orhydroxycarbonyl C₁₋₅ alkyl,

--(CH₂)_(s) C.tbd.CH,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkyl,

--(CH₂)_(s) C.tbd.C--C₃₋₇ cycloalkyl,

--(CH₂)_(s) C.tbd.C-aryl,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkylaryl,

--(CH₂)_(s) CH═CH₂,

--(CH₂)_(s) CH═CH C₁₋₆ alkyl,

--(CH₂)_(s) CH═CH--C₃₋₇ cycloalkyl,

--(CH₂)_(s) CH═CH aryl,

--(CH₂)_(s) CH═CH C₁₋₆ alkylaryl,

--(CH₂)_(s) SO₂ C₁₋₆ alkyl, or

--(CH₂)_(s) SO₂ C₁₋₆ alkylaryl;

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

arylamino,

arylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

C₁₋₆ dialkylamino,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₆ alkylaminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonylamino,

C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonylamino,

aryl C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminosulfonylamino,

C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

arylaminosulfonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

arylaminocarbonyl C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonyl, or

aryl C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

hydroxy,

C₁₋₈ alkoxy,

aryloxy,

aryl C₁₋₆ alkoxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

C₁₋₈ alkylaminocarbonylmethyleneoxy, or

C₁₋₈ dialkylaminocarbonylmethyleneoxy;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6; and

s is an integer from 0 to 3;

and the pharmaceutically acceptable salts thereof.

An additional illustration of the invention is a compound of the formula##STR31## wherein X is a 9- to 10-membered polycyclic ring system,wherein one or more of the rings is aromatic, and wherein the polycyclicring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstituted orsubstituted on a carbon atom with R¹ and R² ;

Y is selected from ##STR32## Z is a 5-11 membered aromatic ornonaromatic mono- or polycyclic ring system containing 0 to 6 doublebonds, and containing 0 to 6 heteroatoms chosen from N, O and S, andwherein the ring system is either unsubstituted or substituted on acarbon or nitrogen atom with one or more groups independently selectedfrom R⁴, R⁵, R⁶ and R⁷ ; provided that Z is not a 6-membered monocyclicaromatic ring system; preferably, Z is selected from ##STR33## R¹, R²,R⁴, R⁵, R¹³ and R¹⁴ are each independently selected from hydrogen,halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino,amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆alkylamino, C₁₋₆ alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl; hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy,hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q),C₁₋₈ aminocarbonyl, C₁₋₈ dialkylaminocarbonyl, C₁₋₈alkyloxycarbonylamino, C₁₋₈ alkylaminocarbonyloxy or C₁₋₈alkylsulfonylamino;

R³ is selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

hydroxyl,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₈ alkylaminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

arylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, or

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ;

R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from

hydrogen,

aryl,

--(CH₂)_(p) -aryl,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

aminocarbonyl,

C₁₋₈ alkylaminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

oxo,

amino,

C₁₋₆ alkylamino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl, either unsubstituted or substituted, with one or more groupsselected from: halogen, hydroxyl, C₁₋₅ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, aminocarbonyl, C₁₋₅ alkylaminocarbonyl,C₁₋₅ alkylcarbonyloxy, C₃₋₈ cycloalkyl, oxo, amino, C₁₋₃ alkylamino,amino C₁₋₃ alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl,aminocarbonyl, aminocarbonyl C₁₋₄ alkyl, hydroxycarbonyl, orhydroxycarbonyl C₁₋₅ alkyl,

--(CH₂)_(s) C.tbd.CH,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkyl,

--(CH₂)_(s) C.tbd.C--C₃₋₇ cycloalkyl,

--(CH₂)_(s) C.tbd.C-aryl,

--(CH₂)_(s) C.tbd.C--C₁₋₆ alkylaryl,

--(CH₂)_(s) CH═CH₂,

--(CH₂)_(s) CH═CH C₁₋₆ alkyl,

--(CH₂)_(s) CH═CH--C₃₋₇ cycloalkyl,

--(CH₂)_(s) CH═CH aryl,

--(CH₂)_(s) CH═CH C₁₋₆ alkylaryl,

--(CH₂)_(s) SO₂ C₁₋₆ alkyl, or

--(CH₂)_(s) SO₂ C₁₋₆ alkylaryl;

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

C₁₋₆ alkylamino C₁₋₆ alkyl,

arylamino,

arylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylamino,

aryl C₁₋₆ alkylamino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

C₁₋₆ dialkylamino,

C₁₋₆ dialkylamino C₁₋₆ alkyl,

C₁₋₆ alkylaminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonylamino,

C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonylamino,

aryl C₁₋₈ alkylaminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminosulfonylamino,

C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

arylaminosulfonylamino C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminosulfonylamino,

aryl C₁₋₈ alkylaminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

arylaminocarbonyl C₁₋₆ alkyl,

aryl C₁₋₈ alkylaminocarbonyl, or

aryl C₁₋₈ alkylaminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups may be unsubstituted or substituted withR¹³ and R¹⁴ ; and provided that the carbon atom to which R⁸ and R⁹ areattached is itself attached to no more than one heteroatom; and providedfurther that the carbon atom to which R¹⁰ and R¹¹ are attached is itselfattached to no more than one heteroatom;

R¹² is selected from

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

hydroxy,

C₁₋₈ alkoxy,

aryloxy,

aryl C₁₋₆ alkoxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkoxy,

C₁₋₈ alkylaminocarbonylmethyleneoxy, or

C₁₋₈ dialkylaminocarbonylmethyleneoxy;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 1 to 4;

q is an integer from 0 to 2;

r is an integer from 0 to 6; and

s is an integer from 0 to 3;

and the pharmaceutically acceptable salts thereof.

More particularly illustrating the invention is a pharmaceuticalcomposition comprising any of the compounds described above and apharmaceutically acceptable carrier. Another example of the invention isa pharmaceutical composition made by combining any of the compoundsdescribed above and a pharmaceutically acceptable carrier. Anotherillustration of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

Further illustrating the invention is a method of treating and/orpreventing a condition mediated by antagonism of a vitronectin receptorin a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds describedabove. Preferably, the condition is selected from bone resorption,osteoporosis, restenosis, diabetic retinopathy, macular degeneration,angiogenesis, atherosclerosis, inflammation, cancer and tumor growth.More preferably, the condition is selected from osteoporosis and cancer.Most preferably, the condition is osteoporosis.

More specifically exemplifying the invention is a method of eliciting avitronectin antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the pharmaceutical compositions described above.Preferably, the vitronectin antagonizing effect is an αvpβ3 antagonizingeffect; more specifically the αvβ3 antagonizing effect is selected frominhibition of bone resorption, inhibition of restenosis, inhibition ofatherosclerosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofinflammation or inhibition of tumor growth. Most preferably, the αvβ3antagonizing effect is inhibition of bone resorption. Alternatively, thevitronectin antagonizing effect is an αvβ5 antagonizing effect or a dualαvβ3/αvβ5 antagonizing effect. Examples of αvβ5 antagonizing effects areinhibition of: restenosis, atherosclerosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation or tumor growth.Examples of dual αvβ3/αvβ5 antagonizing effects are inhibition of: boneresorption, restenosis, atherosclerosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation or tumor growth.

Additional examples of the invention are methods of inhibiting boneresorption and of treating and/or preventing osteoporosis in a mammal inneed thereof, comprising administering to the mammal a therapeuticallyeffective amount of any of the compounds or any of the pharmaceuticalcompositions described above.

Further exemplifying the invention is any of the compositions describedabove, further comprising a therapeutically effective amount of a secondbone resorption inhibitor; preferably, the second bone resorptioninhibitor is alendronate.

More particularly illustrating the invention is any of the methods oftreating and/or preventing osteoporosis and/or of inhibiting boneresoption described above, wherein the compound is administered incombination with a second bone resorption inhibitor; preferably, thesecond bone resorption inhibitor is alendronate.

Additional illustrations of the invention are methods of treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

More particularly exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of osteoporosis in a mammal in need thereof.Still further exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of: bone resorption, tumor growth, cancer,restenosis, atherosclerosis, diabetic retinopathy, macular degeneration,inflammation and/or angiogenesis.

Additional illustrations of the invention are methods of treating tumorgrowth in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of a compound described aboveand one or more agents known to be cytotoxic or antiproliferative, e.g.,taxol and doxorubicin.

DETAILED DESCRIPTION OF THE INVENTION

Representative compounds of the present invention are integrinantagonists which display submicromolar affinity for the human αvβ3receptor. Compounds of this invention are therefore useful for treatingmammals suffering from a bone condition caused or mediated by increasedbone resorption, who are in need of such therapy. Pharmacologicallyeffective amounts of the compounds, including pharamaceuticallyacceptable salts thereof, are administered to the mammal, to inhibit theactivity of mammalian osteoclasts.

The compounds of the present invention are administered in dosageseffective to antagonize the αvβ3 receptor where such treatment isneeded, as, for example, in the prevention or treatment of osteoporosis.For use in medicine, the salts of the compounds of this invention referto non-toxic "pharmaceutically acceptable salts." Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their pharmaceutically acceptable salts. Saltsencompassed within the term "pharmaceutically acceptable salts" refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid. Representative salts include the following:

Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammoniumsalt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate,Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide and Valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts.

The compounds of the present invention, may have chiral centers andoccur as racemates, racemic mixtures, diastereomeric mixtures, and asindividual diastereomers, or enantiomers with all isomeric forms beingincluded in the present invention. Therefore, where a compound ischiral, the separate enantiomers, substantially free of the other, areincluded within the scope of the invention; further included are allmixtures of the two enantiomers. Also included within the scope of theinvention are polymorphs and hydrates of the compounds of the instantinvention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term "administering"shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in "Design of Prodrugs," ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

The term "therapeutically effective amount" shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought by aresearcher or clinician.

The term "vitronectin receptor antagonist," as used herein, refers to acompound which binds to and antagonizes either the αvβ3 receptor or theαvβ5 receptor, or a compound which binds to and antagonizes both theαvβ3 and αvβ5 receptors (i.e., a dual αvβ3/αvβ5 receptor antagonist).

The term "bone resorption," as used herein, refers to the process bywhich osteoclasts degrade bone.

The term "alkyl" shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term "cycloalkyl" shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

The term "cycloheteroalkyl," as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, piperazinyl.

The term "alkoxy," as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term "aryl," as used herein, refers to a monocyclic or polycyclicsystem composed of 5- and 6-membered fully unsaturated or partiallyunsaturated rings, such that the system comprises at least one fullyunsaturated ring, wherein the rings contain 0, 1, 2, 3 or 4 heteroatomschosen from N, O or S, and either unsubstituted or substituted with oneor more groups independently selected from hydrogen, halogen, C₁₋₁₀alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl,C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆alkylamino C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆ dialkylamino-C₁₋₈ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano,trifluoromethyl, oxo or C₁₋₅ alkylcarbonyloxy. Examples of aryl include,but are not limited to, phenyl, naphthyl, pyridyl, pyrazinyl,pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, furyl,dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl, isoxazolyl andthiazolyl, which are either unsubstituted or substituted with one ormore groups independently selected from hydrogen, halogen, C₁₋₁₀ alkyl,C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano,trifluoromethyl, oxo or C₁₋₅ alkylcarbonyloxy. Preferably, the arylgroup is unsubstituted, mono-, di-, tri- or tetra-substituted with oneto four of the above-named substituents; more preferably, the aryl groupis unsubstituted, mono-, di- or tri-substituted with one to three of theabove-named substituents; most preferably, the aryl group isunsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

Whenever the term "alkyl" or "aryl" or either of their prefix rootsappear in a name of a substituent (e.g., aryl C₀₋₈ alkyl) it shall beinterpreted as including those limitations given above for "alkyl" and"aryl." Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherealkyl is as defined above and to include an aryl portion where aryl isas defined above. The C_(0-m) or C_(1-m) designation where m may be aninteger from 1-10 or 2-10 respectively refers to the alkyl component ofthe arylalkyl or alkylaryl unit. Examples of arylalkyl include, but arenot limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl,phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl,thienylethyl, and thienylpropyl. Examples of alkylaryl include, but arenot limited to, toluene, ethylbenzene, propylbenzene, methylpyridine,ethylpyridine, propylpyridine and butylpyridine.

When substituent R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³or R¹⁴ includes the definition C₀ (e.g., aryl C₀₋₈ alkyl), the groupmodified by C₀ is not present in the substituent. Similarly, when any ofthe variables m, q, r or s is zero, then the group modified by thevariable is not present; for example, when s is zero, the group"--(CH₂)_(s) C.tbd.CH" is "--C.tbd.CH". In addition, the substituent"(C₁₋₆ alkyl)_(q) amino" where q is zero, one or two, refers to anamino, C₁₋₆ alkylamino and C₁₋₆ dialkylamino group, respectively. When aC₁₋₆ dialkylamino substituent is intended, the C₁₋₆ alkyl groups can bethe same (e.g., dimethylamino) or different (e.g., N(CH₃)(CH₂ CH₃)).Similarly, the substituent "(aryl)_(q) amino" or ["(aryl C₁₋₆ alkyl)_(q)amino"], where q is zero, one or two, refers to an amino, arylamino anddiarylamino group, [or an amino, aryl C₁₋₆ alkylamino or di-(aryl C₁₋₆alkyl)amino] respectively, where the aryl [or aryl C₁₋₆ alkyl] groups ina diarylamino [or di-(aryl C₁₋₆ alkyl)amino] substituent can be the sameor different.

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur(S) atom. The term "oxo" shall mean ═O.

The term "substituted" shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to ##STR34##

The present invention is also directed to combinations of the compoundsof the present invention with one or more agents useful in theprevention or treatment of osteoporosis. For example, the compounds ofthe instant invention may be effectively administered in combinationwith effective amounts of other agents used in the treatment ofosteoporosis such as bisphosphonate bone resorption inhibitors;preferably, the bone resorption inhibitor is the bisphosphonatealendronate, now sold as FOSAMAX®. Preferred combinations aresimultaneous or alternating treatments of an αvβ3 receptor antagonist ofthe present invention and FOSAMAX®.

In addition, the integrin (αvβ3) antagonist compounds of the presentinvention may be effectively administered in combination with a growthhormone secretagogue in the therapeutic or prophylactic treatment ofdisorders in calcium or phosphate metabolism and associated diseases.These diseases include conditions which can benefit from a reduction inbone resorption. A reduction in bone resorption should improve thebalance between resorption and formation, reduce bone loss or result inbone augmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions. These diseases include: osteoporosis (includingestrogen deficiency, immobilization, glucocorticoid induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcemia, metastatic bone disease, periodontaldisease, cholelithiasis, nephrolithiasis, urolithiasis, urinarycalculus, hardening of the arteries (sclerosis), arthritis, bursitis,neuritis and tetany. Increased bone resorption can be accompanied bypathologically high calcium and phosphate concentrations in the plasma,which would be alleviated by this treatment. Similarly, the presentinvention would be useful in increasing bone mass in patients withgrowth hormone deficiency. Thus, preferred combinations are simultaneousor alternating treatments of an αvβ3 receptor antagonist of the presentinvention and a growth hormone secretagogue, optionally including athird component comprising FOSAMAX®.

In addition, the vitronectin receptor antagonist compounds of thepresent invention may be effectively administered in combination withone or more agents known to be cytoxic or antiproliferative, e.g, taxoland doxorubicin.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term "administering" is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating αvβ3 relatedconditions includes in principle any combination with any pharmaceuticalcomposition useful for treating osteoporosis.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixers, tinctures, suspensions, syrups and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous,intramuscular or transdermal (e.g., patch) form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts. Aneffective but non-toxic amount of the compound desired can be employedas an αvβ3 inhibitor.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, andmost preferably 0.1 to 5.0 mg/kg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A medicament typically containsfrom about 0.01 mg to about 500 mg of the active ingredient, preferably,from about 1 mg to about 100 mg of active ingredient. Intravenously, themost preferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittant throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as `carrier` materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

In the schemes and examples below, various reagent symbols andabbreviations have the following meanings:

AcOH: Acetic acid.

BH₃ ·DMS: Borane·dimethylsulfide.

BOC(Boc): t-Butyloxycarbonyl.

BOP: Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate.

CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl.

CDI: Carbonyldiimidazole.

CH₂ Cl₂ : Methylene chloride.

CHCl₃ : Chloroform.

DEAD: Diethyl azodicarboxylate.

DIAD: Diisopropyl azodicarboxylate.

DIBAH or DIBAL-H: Diisobutylaluminum hydride.

DIPEA: Diisopropylethylamine.

DMAP: 4-Dimethylaminopyridine.

DME: 1,2-Dimethoxyethane.

DMF: Dimethylformamide.

DMSO: Dimethylsulfoxide.

DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate.

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.

EtOAc: Ethyl acetate.

EtOH: Ethanol.

HOAc: Acetic acid.

HOAT: 1-Hydroxy-7-azabenzotriazole

HOBT: 1-Hydroxybenzotriazole.

LDA: Lithium diisopropylamide.

MeOH: Methanol.

NEt₃ : Triethylamine.

NMM: N-methylmorpholine.

PCA·HCl: Pyrazole carboxamidine hydrochloride.

Pd/C: Palladium on activated carbon catalyst.

Ph: Phenyl.

pTSA p-Toluene sulfonic acid.

TEA: Triethylamine.

TFA: Trifluoroacetic acid.

THF: Tetrahydrofuran.

TLC: Thin Layer Chromatography.

TMEDA: N,N,N',N'-Tetramethylethylenediamine.

TMS: Trimethylsilyl.

The novel compounds of the present invention were prepared according tothe procedure of the following schemes and examples, using appropriatematerials and are further exemplified by the following specificexamples. The most preferred compounds of the invention are any or allof those specifically set forth in these examples. These compounds arenot, however, to be construed as forming the only genus that isconsidered as the invention, and any combination of the compounds ortheir moieties may itself form a genus. The following examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures aredegrees Celsius unless otherwise noted.

The following Schemes and Examples describe procedures for makingrepresentative compounds of the present invention. Moreover, byutilizing the procedures described in detail in PCT InternationalApplication Publication Nos. WO95/32710, published Dec. 7, 1995, andWO95/17397, published Jun. 29, 1995, in conjunction with the disclosurecontained herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein.

More specifically, procedures for preparing the N-terminus of thecompounds of the present invention are described in WO 95/32710.Additionally, for a general review describing the synthesis ofβ-alanines which can be utilized as the C-terminus of the compounds ofthe present invention, see Cole, D. C., Recent Stereoselective SyntheticApproaches to β-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi,E, et al., Enantioselective Synthesis of β-Amino Acids, AldrichemicaActa, 1994, 27, 3. In particular, synthesis of the 3-methyl β-alanine istaught in Duggan, M. F. et al., J. Med. Chem., 1995, 38, 3332-3341; the3-ethynyl β-alanine is taught in Zablocki, J. A., et al., J. Med. Chem.,1995, 38, 2378-2394; the 3-pyrid-3-yl β-alanine is taught in Rico, J. G.et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino and2-toslylamino β-alanines are taught in Xue, C-B, et al., Biorg. Med.Chem. Letts., 1996, 6, 339-344. ##STR35## 2-Oxo-3-(3-oxobutyl)piperidine(1-3)

A stirred solution of TMEDA (3.0 g, 20 mmol), 0.5 M LDA (6 mL, in THF),and THF (10 mL) at -78° C. was treated with 1-1 (1.7 g, 10 mmol) (forpreparation, see: JOC, 1990, 55, 3682) to effect an orange solution.

After 1 h, the iodide 1-2 (2.4 g, 10 mmol) (J. Org. Chem., 1983, 48,5381) was added to the orange solution and the resulting solutionstirred for 2 h at -78° C., 3 h at -15° C. and then 16 h at ambienttemperature. The reaction mixture was concentrated and then treated with1N HCl (30 mL). The mixture was then basified with 1N NaOH/brinefollowed by extraction with EtOAc (3×). The combined extracts were dried(MgSO₄) and concentrated to give a yellow oil. Flash chromatography(silica, EtOAc→10% CH₃ OH/EtOAc) gave 1-3 as a colorless solid.

TLC R_(f) 0.42 (silica, 10% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ5.75 (bs, 1H), 3.28 (m, 2H), 2.64 (t, 7 Hz, 2H), 2.30-1.50 (m, 7H), 2.16(s, 3H).

2-Oxo-3-[2-([1,8]-naphthyridin-2-yl)ethyl]piperidine (1-5)

A solution of 1-3 (0.25 g, 1.5 mmol), L-proline (85 mg, 0.75 mmol), 1-4(0.18 g, 1.5 mmol) (for preparation see: Synth. Commun. 1987, 17, 1695),and ethanol (10 mL) was refluxed for 24 hr. The cooled solution wasconcentrated and the residue purified by flash chromatography (silica,EtOAc→20% CH₃ OH/EtOAc) to give 1-5 as a solid.

TLC R_(f) =0.32 (silica, 20% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ9.08 (m, 1H), 8.16 (m, 1H), 8.10 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H),7.45 (m, 1H), 5.64 (bs, 1H), 3.31 (m, 2H), 3.18 (m, 2H), 2.50-1.60 (m,7H).

Ethyl 2-Oxo-3-[2-([1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetate(1-6)

A solution of 1-5 (0.28 g, 1.1 mmol) and DMF (10 mL) at -15° C. wastreated with NaN(TMS)₂ (1.2 mL, 1.2 mmol, 1M in hexanes) to give a redsolution. After 30 min, the red solution was treated with ethylbromoacetate (128 μL, 1.2 mmol), followed by continued stirring for 1 h.The reaction mixture was then quenched with sat. NH₄ Cl and thenextracted with EtOAc (3×). The combined extracts were washed with brine,dried (MgSO₄), and concentrated. Flash chromatography (silica, 10% CH₃OH/EtOAc) gave 1-6 as a yellow gum.

TLC R_(f) =0.50 (silica, 10% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ9.07 (m, 1H), 8.16 (m, 1H), 8.10 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H),7.44 (m, 1H), 4.30-3.90 (m, 4H), 3.50-3.30 (m, 2H), 3.17 (m, 2H), 2.46(m, 2H), 2.20-1.70 (m, 5H), 1.28 (t, J=7 Hz, 3H).

Ethyl2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetate(1-7)

A mixture of 1-6 (102 mg, 0.3 mmol), 10% Pd/C (50 mg), and EtOAc (25 mL)was stirred under a hydrogen atmosphere (1 atm) for 24 h. The catalystwas then removed by filtration through celite and the filtrateconcentrated. Flash chromatography (silica, 20% CH₃ OH/EtOAc) gave 1-7as a yellow gum.

TLC R_(f) =0.45 (silica, 30% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ7.05 (d, J=6 Hz, 1H), 6.41 (d, J=6 Hz, 1H), 4.80 (bs, 1H), 4.18 (q, J=7Hz, 2H), 4.08 (m, 2H), 3.37 (m, 4H), 2.80-1.60 (m, 13H), 1.26 (t, 7 Hz,3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-aceticacid (1-8)

A solution of 1-7 (71 mg, 0.21 mmol) and 6N HCl (15 mL) was stirred at55° C. for 2 h, followed by concentration to give 1-8 as a pale yellowgum. TLC R_(f) =0.09 (silica, 20% CH₃ OH/EtOAc)

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)ethyl]piper-idin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester (1-10)

A stirred mixture of 1-8 (71 mg, 0.20 mmol), 1-9 (59 mg, 0.22 mmol)(Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (88 μL, 0.8 mmol), andCH₃ CN (25 mL) was treated with BOP (97 mg, 0.22 mmol). After 24 h, thereaction mixture was concentrated to dryness, dissolved in EtOAc, andthen washed with H₂ O, dried (MgSO₄), and concentrated. Flashchromatography (silica, 10% (NH₃ /EtOH/EtOAc) gave 1-10 as a colorlessgum.

TLC R_(f) =0.9 (silica, 10% (NH₃ /EtOH)/EtOAc); ¹ H NMR (300 MHz, CD₃OD) δ 8.55 (m, 1H), 8.43 (m, 1H), 7.83 (m, 1H), 7.40 (m, 1H), 7.11 (m,1H), 6.37 (m, 1H), 5.38 (m, 1H), 4.08 (q, J=7 Hz, 2H), 4.00 (m, 2H),3.37 (m, 4H), 2.90 (m, 1H), 2.70-1.60 (m, 14H), 1.14 (t, J=7 Hz, 3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alaninetrifluoroacetate (1-11)

A stirred solution of 1-11 (52 mg, 0.10 mmol) and 6N HCl (10 mL) washeated at 55° C. for 2 h, followed by concentration.

Preparative HPLC (VYDAC C₁₈ semiprep column, gradient elution: [95:5(0.1% TFA/H₂ O/0.1% TFA/CH₃ CN) to 50:50 (0.1% TFA/H₂ O/0.1% TFA/CH₃ CN)80 min] gave 1-11 as a colorless solid.

¹ H NMR (300 MHz, CD₃ OD) δ 8.90 (s, 1H), 8.74 (d, J=5 Hz, 1H), 8.61 (d,J=8 Hz, 1H), 8.03 (m, 1H), 7.56 (d, J=7 Hz, 1H), 6.59 (d, J=7 Hz, 1H),5.43 (m, 1H), 4.03 (m, 2H), 3.40 (m, 5H), 3.00 (m, 2H), 2.78 (m, 4H),2.40-1.60 (m, 12H). ##STR36##(2-Oxo-3-(3-(ethylendioxy)butyl)pyrrolidin-1-yl)benzyl (2-2)

To a stirred solution of 2-1 (5.3 g, 30 mmol) and THF (100 mL) at -78°C. was added LDA (17.5 mL, 35 mmol, 2.0 M in hexanes) dropwise over a 10minute period. After 30 min, 1-2 (5.0 g, 21 mmol) was added followed byremoval of the cooling bath. After 1 h, the reaction was quenched withAcOH (10 mL) and then diluted with EtOAc, washed with sat. NaHCO₃ andbrine, dried (MgSO₄) and concentrated. Flash chromatography (silica,25%→75% EtOAc/hexanes) gave 2-2 as an oil.

TLC R_(f) =0.38 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 7.25 (m,5H), 4.48 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 3.94 (s, 4H), 3.18(m, 2H), 2.44 (m, 1H), 2.30-1.30 (m, 9H).

2-Oxo-3-(3-(ethylendioxy)butyl)pyrrolidine (2-3)

To a stirred solution of 2-2 (4.1 g, 14.2 mmol) in THF (100 mL) at -78°C. was added a solution of Li 4,4'-di-tert-butylbiphenyl (188 mL, 0.5 Min THF) in 4 portions. After 1 h, the reaction was quenched with AcOH(25 mL). The resulting mixture was diluted with EtOAc and then washedwith H₂ O, sat. NaHCO₃, and brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, EtOAc→10% CH₃ OH/EtOAc) gave 2-3 as a yellowoil.

TLC R_(f) =0.1 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 6.23 (bs,1H), 3.94 (s, 4H), 3.30 (m, 2H), 2.70 (m, 2H), 2.10-1.30 (m, 9H).

Ethyl (2-Oxo-3-(3-(ethylendioxy)butyl)pyrrolidin-1-yl)acetate (2-4)

To a rapidly stirred solution of 2-3 (0.86 g, 4.3 mmol) and THF (25 mL)at -78° C. was added NaN(TMS)₂ (5.2 mL, 5.2 mmol, 1.0 M in THF). After20 min, ethyl bromoacetate (0.58 mL, 5.2 mmol) was added followed byremoval of the cooling bath. After 1 h, the reaction mixture was dilutedwith EtOAc and then washed with H₂ O, sat. NaHCO₃ and brine, dried(MgSO₄), and concentrated to give 2-4 as a yellow oil.

TLC R_(f) =0.53 (silica, EtOAc); ¹ H NMR (300 MHz, CDC₁₃) δ 4.18 (q, J=7Hz, 2H), 4.04 (m, 2H), 3.93 (s, 4H), 3.39 (m, 2H), 2.44 (m, 1H), 2.23(m, 1H), 2.00-1.30 (m, 9H), 1.25 (t, J=7H, 3H).

Ethyl (2-Oxo-3-(3-oxobutyl)pyrrolidin-1-yl)acetate (2-5)

A solution of 2-4 (1.1 g, 3.9 mmol), p-TSA (5 mg) and acetone (50 mL)was heated at reflux for 1 hr. The cooled reaction mixture was dilutedwith EtOAc and then washed with sat. NaHCO₃ and brine, dried (MgSO₄),and concentration to afford 2-5 as a yellow oil.

TLC R_(f) =0.48 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 4.18 (q, J=7Hz, 2H), 4.01 (s, 2H), 3.40 (m, 2H), 2.67 (t, J=7 Hz, 2H), 2.48 (m, 1H),2.30-1.60 (m, 4H), 2.15 (s, 3H), 1.25 (t, J=7 Hz, 3H).

Ethyl (2-Oxo-3-(2-([1,8]naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-acetate(2-6)

A mixture of 2-5 (0.77 g, 3.0 mmol), 1-4 (0.55 g, 4.5 mmol, forpreparation see Het, 1993, 36, 2513), L-proline (0.17 g, 1.5 mmol) andethanol (25 mL) was heated at reflux for 20 hr. The cooled reactionmixture was concentrated and the residue purified by flashchromatography (silica, EtOAc→5% CH₃ OH/EtOAc) to give 2-6 as a yellowoil.

TLC R_(f) =0.13 (silica, 10% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ9.08 (m, 1H), 8.17 (m, 1H), 8.12 (d, J=8 Hz, 1H), 7.49 (d, J=8 Hz, 1H),7.46 (m, 1H), 4.15 (q, J=7 Hz, 2H), 4.04 (m, 2H), 3.42 (m, 2H), 3.21 (t,J=8 Hz, 2H), 2.60-1.80 (m, 5H), 1.25 (t, J=7 Hz, 3H).

Ethyl(2-Oxo-3-(2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)acetate(2-7)

A mixture of 2-6 (0.87 g, 2.6 mmol), 10% Pd/C (0.5 g), and CH₃ OH (25mL) was stirred under a hydrogen atmosphere (1 atm) for 2 hr. Thecatalyst was then removed by filtration through a celite pad followed byconcentration of the filtrate. Flash chromatogrphy (silica, EtOAc→5% CH₃OH/EtOAc) gave 2-7 as a yellow oil.

TLC R_(f) =0.18 (silica, 5% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ7.05 (d, J=7 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 4.83 (bs, 1H), 4.17 (q, J=7Hz, 2H), 4.03 (m, 2H), 3.40 (m, 4H), 2.80-1.60 (m, 11H), 1.27 (t, J=7Hz, 3H).

(2-Oxo-3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)aceticacid hydrochloride (2-8)

A stirred mixture of 2-7 (0.45 g, 1.4 mmol) and 6N HCl (10 mL) washeated at 50° C. for 1 h, followed by concentration to give 2-8 as ayellow oil.

¹ H NMR (300 MHz, CD₃₀ D) δ 7.60 (d, J=7 Hz, 1H), 6.66 (d, J=7 Hz, 1H),4.05 (s, 2H), 3.50 (m, 4H), 2.83 (m, 4H), 2.54 (m, 1H), 2.32 (m, 1H),2.10 (m, 1H), 2.00-1.75 (m, 4H).

(2-Oxo-3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester (2-11)

To a stirred solution of 2-8 (50 mg, 0.15 mmol), 2-9 (29 mg, 0.17 mmol)(Zablocki et al., J. Med Chem., 1995, 38, 2378), NMM (83 μL, 0.75 mmol),and CH₃ CN (1 mL) was added BOP (74 mg, 0.17 mmol). After 20 h, thereaction mixture was diluted with EtOAc and then washed with sat.NaHCO₃, H₂ O and brine, dried (MgSO₄), and concentrated to give 2-11 asa yellow oil.

TLC R_(f) =0.24 (silica, 10% CH₃ OH/EtOAc).

(2-Oxo-3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester (2-12)

To a stirred solution of 2-8 (50 mg, 0.15 mmol), 2-10 (44 mg, 0.17 mmol)(Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (83 μL, 0.75 mmol),and CH₃ CN (1 mL) was added BOP (74 mg, 0.17 mmol). After 20 h, thereaction mixture was diluted with EtOAc and then washed with sat.NaHCO₃, H₂ O and brine, dried (MgSO₄), and concentrated to give 2-12 asa brown oil.

TLC R_(f) =0.24 (silica, 20% CH₃ OH/EtOAc).

(2-Oxo-3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine(2-13)

A mixture of 2-11 (0.1 g, 0.15 mmol), 1N NaOH (300 μL, and ethanol (1mL) was stirred at ambient temperature for 1 hr. Concentration and thenflash chromatography (silica, 25:10:1:1→15:10:1:1 EtOAc/EtOH/NH₄ OH/H₂O) gave 2-13 as a white solid.

TLC R_(f) =0.18 (silica, 10:10:1:1 EtOAc/EtOH/NH₄ OH/H₂ O); ¹ H NMR (300MHz, CD₃ OD) δ 7.45 (m, 1H), 6.50 (m, 1H), 4.53 (m, 1H), 3.80-3.30 (m,5H), 3.05 (m, 1H), 2.80-2.15 (m, 9H), 2.00-1.75 (m, 4H).

(2-Oxo-3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine(2-14)

A mixture of 2-12 (0.1 g, 0.15 mmol), 1N NaOH (300 μL) and ethanol (1mL) was stirred at ambient temperature for 1 hr. Concentration and theflash chromatography (silica, 25:10:1:1→15:10:1:1 EtOAc/EtOH/NH₄ OH/H₂O) gave 2-14 as a white solid.

TLC R_(f) =0.10 (silica, 10:10:1:1 EtOAc/EtOH/NH₄ OH/H₂ O); ¹ H NMR (300MHz, CD₃ OD) δ 8.57 (m, 1H), 8.40 (m, 1H), 7.86 (m, 1H), 7.40 (m, 2H),6.50 (m, 1H), 5.28 (m, 1H), 4.65-4.40 (m, 1H), 3.90-1.80 (M, 19H).##STR37## 4-(Propyl-2-ene)butyric acid (3-2)

To a stirred suspension of of methyltriphenylphosphonium bromide (67.7g, 190 mmol) in 1 L THF at 0° C. was added a solution of sodiumbis(trimethylsilyl)amide (190 mL, 190 mmol, 1M THF). After an additional30 minutes, 3-1 ethyl 4-acetylbutyrate (Aldrich Chemical Co.)(25.0 g,158 mmol) was added, and the mixture stirred for 18 h. The mixture wasfiltered, and the filtrate concentrated. The residue was triturated withhexanes, and then filtered. Following evaporative removal of thesolvent, the residue was chromatographed on silica gel, eluting with 10%ethyl acetate/hexanes to give the olefin as a colorless oil. TLC R_(f)=0.52 (10% ethyl acetate/hexanes).

¹ H NMR (300 MHz, CHCl₃) δ 4.71 (d, 2H, J=13 Hz), 4.13 (q, 2H, J=7 Hz),2.29 (t, 2H, J=7 Hz), 2.05 (t, 2H, J=8 Hz), 1.77 (m, 2H), 1.72 (s, 3H),1.26 (t, 3H, J=7 Hz).

A solution of the above olefin (15.4 g, 98.6 mmol), 1 N NaOH (150 mL),and EtOH (300 mL) was stirred at ambient temperature for 2 h. Followingacidification with 1 N HCl, the mixture was extracted with ether. Theether layer was washed with brine, dried over magnesium sulfate, andconcentrated to give 3-2 as a colorless oil.

¹ H NMR (300 MHz, CHCl₃) δ 4.70 (d, 2H, J=13 Hz), 2.27 (t, 2H, J=7 Hz),2.06 (t, 2H, J=7 Hz), 1.72 (m, 5H).

(4-(Propyl-2-ene)butanoyl)4(R)-benzyl-2-oxazolidinone (3-3)

To a solution of 3-2 (6.0 g , 46.8 mmol) in THF (200 ml) at -78° C. wasadded triethylamine (7.19 mL , 51.5 mmol) followed by pivaloyl chloride(6.35 mL , 51.5 mmol). The mixture was warmed to 0° C. for 1 h, thenrecooled to -78° C. In a separate flask, of(R)-(+)-4-benzyl-2-oxazolidinone (9.15 g, 51.5 mmol) was dissolved inTHF (100 mL), cooled to -78° C., and n-BuLi (32.3 mL, 51.5 mmol; 1.6 Mhexanes) was added dropwise. After 10 minutes, the lithium oxazolidinonewas added to the pivalic anhydride. After 10 minutes, the mixture waswarmed to 0° C. for 1.5 h. The mixture was then poured into ethylacetate, washed with aqueous sodium bicarbonate, and dried overmagnesium sulfate. Following evaporative removal of the solvent, theresidue was chromatographed (silica gel, dichloromethane) to give 3-3 asa slightly yellow oil.

TLC R_(f) =0.8 (CH₂ Cl₂). ¹ H NMR (300 MHz, CHCl₃) δ 7.40-7.18 (m, 5H),4.80-4.60 (m, 3H), 4.18 (m, 2H), 3.30 (dd, 1H, J=3.2, 13.2 Hz), 2.95 (m,2H), 2.76 (dd, 1H, J=9.5, 13.1 Hz), 2.11 (t, 2H, J=7.5 Hz), 1.87 (m,2H), 1.74 (s, 3H).

2-Chloroethyltriflate (3-4)

To a solution of 1.67 mL (24.8 mmol) of 2-chloroethanol and 3.47 mL(29.8 mmol) of 2,6-lutidine in 20 mL of dichloromethane at 0° C. wasadded 4.59 mL (27.3 mmol) of triflic anhydride. After 1 h, the mixturewas diluted with hexanes, washed with ice-cold 1 N HCl, and dried oversodium sulfate. The solvents were evaporated to give 3-4 as a pink oil.

¹ H NMR (300 MHz, CHCl₃) δ 4.69 (t, 2H, J=5.3 Hz), 3.78 (t, 2H, J=5.6Hz).

2(S)-Chloroethyl-4-(propyl-2-ene)butanoyl-(4(R)-benzyl-2-oxazolidinone)(3-5)

To a solution of 3-3 (11.0 g, 38.3 mmol) in THF (60 mL) at -78° C. wasadded a solution of sodium bis(trimethylsilyl)amide (42.1 mL, 42.1 mmol;1M/THF). After 20 min, 3-4 (16.2 ml, 115 mmol) was added over 5 min, andthe resulting mixture stirred for 1.5 h at -78° C., then 2 h at -150 C.The mixture was diluted with hexanes, washed with sat. ammoniumchloride, and dried over sodium sulfate. Following evaporative removalof the solvent, the residue was chromatographed (silica gel, 14% ethylacetate/hexanes) to give 3-5 as a colorless oil. TLC R_(f) =0.5 (20%ethyl acetate/hexanes).

¹ H NMR (300 MHz, CHCl₃) δ 7.30-7.18 (m, 5H), 4.67 (m, 3H), 4.19 (m,2H), 3.99 (m, 1H), 3.58 (m, 2H), 3.33 (dd, 1H, J=3.2, 12.0 Hz), 2.75(dd, 1H, J=9.7, 13.5 Hz), 2.23 (m, 1H), 2.18-1.82 (m, 4H), 1.77-1.60 (m,1H), 1.71 (s, 3H).

Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidine (3-6)

A mixture of 3-5 (8.15 g, 23.3 mmol) and NaN₃ (4.54 g, 69.8 mmol) inDMSO (120 mL) was heated at 750° C. for 2 h. After cooling, the mixturewas diluted with ether and hexanes, washed with water, and dried oversodium sulfate. Evaporative removal of the solvent gave the azide as acolorless oil.

TLC R_(f) =0.5 (20% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ7.30-7.22 (m, 5H), 4.69 (m, 3H), 4.17 (d, 2H, J=5.1 Hz), 3.89 (m, 1H),3.38 (m, 3H), 2.74 (m, 1H), 2.13-1.63 (m, 6H), 1.71 (s, 3H).

To a solution of of this azide (8.0 g , 22.4 mmol) in THF (250 mL) andwater (40 mL) was added triphenylphosphine (8.24 g, 31.4 mmol) in 4portions over 5 minutes. This mixture was heated at reflux for 2 h,cooled, and evaporated. The residue was chromatographed (silica gel, 10%chloroform/ethyl acetate) to give 3-6 as a colorless oil.

TLC R_(f) =0.40 (20% chloroform/ethyl acetate). ¹ H NMR (300 MHz, CHCl₃)δ 6.47 (br s, 1H), 4.73 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.08 (m,3H), 1.81 (m, 1H), 1.74 (s, 3H), 1.44 (s, 1H).

Ethyl 2-oxo-3(S)-(3-methylenebutyl)pyrrolidin-1-yl)acetate (3-7)

To a solution of 3-6 (2.50 g, 16.3 mmol) in THF (40 mL) at -78° C. wasadded sodium bis(trimethylsilyl)amide (17.1 mL, 17.1 mmol; 1M/THF)dropwise. After an additional 20 min, ethyl bromoacetate (2.17 mL, 19.6mmol) was added dropwise over 3 min. After an additional 20 min, 20 mLsat. aqueous NH₄ Cl was added, and the cooling bath removed. The layerswere separated, the aqueous layer washed with ether, and the combinedorganic extracts were dried over sodium sulfate. Following evaporativeremoval of the solvent, the residue was chromatographed (silica gel, 40%ethyl acetate/hexanes) to give 3-7 as a colorless oil.

TLC R_(f) =0.85 (50% chloroform/ethyl acetate). ¹ H NMR (300 MHz, CHCl₃)δ 4.73 (m, 2H), 4.18 (q, 2H, J=7.1 Hz), 4.06 (dd, 2H, J=17.6, 20.8 Hz),3.42 (m, 2H), 2.44 (m, 1H), 2.27 (m, 1H), 2.12 (m, 3H), 1.75 (m, 1H),1.74 (s, 3H), 1.50 (m, 1H), 1.28 (t, 3H, J=7.3 Hz).

Ethyl 2-oxo-3(S)-(3-oxo-butyl)pyrrolidin-1-yl)acetate (3-8)

To a solution of 3-7 (3.35 g,14.0 mmol) and N-methylmorpholine-N-oxide(3.27 g, 28.0 mmol) in THF (10 mL) and water (1 mL) was added OsO₄ (5.7mL, 0.56 mmol; 2.5% t-butanol). After 1 h, NaIO₄ (5.99 g, 28 mmol) inwarm water (30 mL) was added over 2 min, and the resulting mixturestirred for 1 h. Water was then added, and the aqueous layer washed withether and ethyl acetate, and the combined organic extracts were driedover sodium sulfate. Evaporative removal of the solvent gave 3-8 as adark oil containing residual OsO₄.

TLC R_(f) =0.78 (70:20:10 chloroform/ethyl acetate/MeOH). ¹ H NMR (300MHz, CHCl₃) δ 4.19 (m, 2H, J=7.2 Hz), 4.03 (s, 2H), 3.41 (m, 2H), 2.68(t, 2H, J=9.4 Hz) 2.45 (m, 1H), 2.27 (m, 1H), 2.17 (s, 3H), 1.97 (m,1H), 1.78 (m, 2H), 1.28 (t, 3H, J=7.2 Hz).

Ethyl2-oxo-3(S)-[2-([1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetate(3-9)

A mixture of 3-8 (3.25 g, 13.5 mmol), 1-4, 2-amino-3-formylpyridine (2.2g, 18.2 mmol; for preparation see Synth. Commun. 1987, 17, 1695) andproline (0.62 g, 5.39 mmol) in absolute ethanol (45 mL) was heated atreflux for 15 h. Following evaporative removal of the solvent, theresidue was chromatographed (silica gel, 70:25:5 chloroform/ethylacetate/MeOH to give 3-9 as a colorless oil.

TLC R_(f) =0.24 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300MHz, CHCl₃) δ 9.08 (m, 1H), 8.16 (m, 2H), 7.47 (m, 2H), 4.17 (m, 4H),3.42 (m, 2H), 3.21 (t, 2H, J=6.0 Hz), 2.56 (m, 1H), 2.39 (m, 2H), 2.08(m, 1H), 1.87 (m, 1H), 1.27 (t, 3H, J=7.1 Hz).

Ethyl2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetate(3-10)

A mixture of 3-9 (3.33 g, 10.2 mmol) and 10% Pd/carbon (1.5 g) in EtOH(50 mL) was stirred under a balloon of hydrogen for 13 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH togive 3-10 as a colorless oil.

TLC R_(f) =0.20 (70:20:10 chloroform/ethyl acetate/MeOH). ¹ H NMR (300MHz, CDCl₃) δ 7.05 (d, 1H, J=7.3 Hz), 6.38 (d, 1H, J=7.3 Hz), 4.88 (brs, 1H), 4.17 (dd, 2H, J=7.0, 14.4 Hz), 4.04 (dd, 2H, J=17.6, 27.3 Hz),3.40 (m, 4H), 2.69 (m, 4H), 2.51 (m, 1H), 2.28 (m, 2H), 1.90 (m, 2H),1.78 (m, 2H), 1.27 (t, 3H, J=6.9 Hz).

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)aceticacid (3-11)

A mixture of 3-10 (0.60 g, 1.81 mmol) and 6N HCl (25 mL) was heated at60° C. for 1 h. Evaporative removal of the solvent gave 3-11 as a yellowoil.

¹ H NMR (300 MHz, DMSO-d₆) δ 8.4 (br s, 1H), 7.60 (d, 1H, J=7.3 Hz),6.63 (d, 1H, J=7.3 Hz), 3.92 (dd, 2H, J=17.6, 25.9 Hz), 3.43 (m, 2H),3.35 (m, 2H), 2.74 (m, 4H), 2.28 (m, 2H), 2.03 (m, 1H), 1.82 (m, 2H),1.67 (m, 2H).

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine;ethyl ester (3-12)

A mixture of 3-11 (0.20 g, 0.588 mmol), 2-9 (0.157 g, 0.882 mmol), EDC(0.147 g, 0.765 mmol), HOBT (0.095 g, 0.706 mmol) and NMM (0.453 mL,4.12 mmol) in CH₃ CN (3 mL) and DMF (2 mL) was stirred for 20 h. Themixture was diluted with ethyl acetate, washed with water, brine, anddried over sodium sulfate. Following evaporative removal of the solvent,the residue was chromatographed (silica gel, 70:20:10 chloroform/ethylacetate/MeOH to give 3-12 as a colorless foam.

TLC R_(f) =0.44 (70:20:10 chloroform/ethyl acetate/MeOH). ¹ H NMR (300MHz, CDCl₃) δ 7.06 (d, 1H, J=7.3 Hz), 6.39 (d, 1H, J=7.3 Hz), 5.07 (m,1H), 4.94 (br s, 1H), 4.18 (q, 2H, J=6.1 Hz), 3.95 (q, 2H, J=16.1 Hz),3.39 (m, 4H), 2.90 (s, 1H), 2.68 (m, 6H), 2.50 (m, 1H), 2.27 (m, 3H),1.82 (m, 4H), 1.27 (t, 3H, J=7.1 Hz).

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-ethnyl-β-alanine(3-13)

To a solution of 3-12 (0.050 g, 0.117 mmol) in EtOH (1 mL) was added 1NNaOH (0.164 ml, 0.164 mmol). After stirring for 2 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 25:10:1:1ethyl acetate/EtOHlwater/NH₄ OH to give 3-13 as a colorless foam.

TLC R_(f) =0.26 (25:10:1:1 ethyl acetate/EtOH/water/NH₄ OH). ¹ H NMR(300 MHz, DMSO-d₆) δ 7.75 (br s, 1H), 7.14 (d, 1H, J=7.3 Hz), 6.31 (d,1H, J=7.3 Hz), 4.74 (m, 1H), 3.90 (d, 1H, J=16.6 Hz), 3.67 (d, 1H,J=16.6 Hz), 3.23 (m, 4H), 2.57 (m, 7H), 2.30 (m, 1H), 2.11 (m, 2H), 1.73(m, 2H), 1.59 (m, 2H).

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester (3-14)

A mixture of 3-11 (0.30 g, 0.882 mmol), 2-10 (0.354 g, 1.32 mmol), EDC(0.220 g (1.15 mmol), HOBT (0.143 g, 1.05 mmol) and NMM (0.680 mL (6.18mmol) in CH₃ CN (5 mL) and DMF (3 mL) at 0° C. was stirred for 10 min,then allowed to warm and stir for 20 h. The mixture was diluted withethyl acetate, washed with water, brine, and dried over sodium sulfate.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH togive 3-14 as a colorless foam.

TLC R_(f) =0.31 (70:20:10 chloroforn/ethyl acetate/MeOH). ¹ H NMR (300MHz, CHCl₃) δ 8.55 (d, 1H, J=2.2 Hz), 8.50 (dd, 1H, J=1.5, 4.6 Hz), 7.64(m, 2H), 7.23 (m, 1H), 7.05 (d, 1H, J=7.3 Hz), 6.38 (d, 1H, J=7.3 Hz),5.40 (m, 1H), 4.98 (br s, 1H), 4.01 (m, 4H), 3.39 (m, 4H), 2.85 (m, 2H),2.68 (m, 4H), 2.49 (m, 1H), 2.25 (m, 2H), 1.83 (m, 4H), 1.16 (t, 3H,J=7.2 Hz).

2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine(3-15)

To a solution of 3-14 (0.049 g, 0.102 mmol) in THF (1 mL) and water (0.3mL) at 0° C. was added 1M LiOH (0.112 ml, 0.112 mmol). After warming toambient temperature and stirring for 2 h, the solvents were evaporatedand the residue was chromatographed (silica gel, 25:10:1:1 ethylacetate/EtOH/water/NH₄ OH to give 3-15 as a colorless foam.

TLC R_(f) =0.15 (25:10:1:1 ethyl acetate/EtOH/water/NH₄ OH). ¹ H NMR(300 MHz, DMSO-d₆) δ 8.74 (d, 1H, J=8.3 Hz), 8.51 (m, 1H), 8.42 (m, 2H),7.70 (d, 1H, J=8.1 Hz), 7.33 (m, 1H), 7.21 (d, 1H, J=7.3 Hz), 6.36 (d,1H, J=7.3 Hz), 5.14 (m, 1H), 4.00 (d, 1H, J=16.8 Hz), 3.70 (d, 1H,J=16.6 Hz), 3.30 (m, 4H), 2.68 (m, 7H), 2.20 (m, 3H), 1.71 (m, 4H).##STR38##2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester (4-2)

Prepared from 4-1 (prepared by the method used to prepare 3-11,utilizing (S)-(-)-4-benzyl-2-oxazolidinone) and 2-9, by the method usedto prepare 3-12.

¹ H NMR (300 MHz, CHCl₃) δ 7.06 (d, 1H, 3=7 Hz), 6.39 (d, 1H), J=7 Hz),5.06 (m, 1H), 4.84 (br s, 1H), 4.16 (q, 2H, J=6 Hz), 3.93 (m, 2H), 3.38(m, 4H), 2.68 (m, 6H), 2.52 (m, 1H), 2.25 (m, 2H), 1.90 (m, 2H), 1.78(m, 2H), 1.26 (t, 3H, J=7 Hz).

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine(4-3)

Prepared from 4-2 (0.05 g, 0.11 mmol) by the method used to prepare3-13.

¹ H NMR (300 MHz, CD₃ OD, 1 drop 1N NaOD) δ 7.11 (d, 1H, J=7 Hz), 6.40(d, 1H, J=7 Hz), 4.90 (m, 1H), 3.94 (q, 2H, J=17 Hz), 3.39 (m, 4H), 2.69(d, 2H, J=6 Hz), 2.60 (m, 2H), 2.52 (d, J=7 Hz), 2.49 (m, 1H), 2.27 (m,1H), 2.13 (m, 1H), 1.85 (m, 4H), 1.68 (m, 1H).

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester (4-4)

Prepared from 4-1 (0.35 g, 1.0 mimol) and 2-10 (0.33 g, 1.2 mmol) by themethod used to prepare 3-14.

¹ H NMR (300 MHz, CHCl₃) δ 8.55 (d, 1H, J=2 Hz), 8.55 (dd, 1H, J=2, 5Hz), 7.61 (m, 1H), 7.54 (m, 1H), 7.06 (d, 1H), 6.38 (d, 1H, J=7 Hz),5.40 (m, 1H), 4.90 (br s, 1H), 4.05 (q, 2H, J=7 Hz), 3.95 (m, 2H), 3.42(m, 4H), 2.85 (dd, 2H, J=2, 6 Hz), 2.67 (m, 4H), 2.53 (m, 1H), 2.27 (m,2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.16 (m, 3H, J=7 Hz).

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine(4-5)

Prepared from 4-4 (0.16 g, 0.33 mmol) by the method used to prepare3-15.

¹ H NMR (300 MHz, CD₃ OD) δ 8.57 (s, 1H), 8.42 (m, 1H), 7.86 (d, 1H, J=6Hz), 7.43 (m, 2H), 6.51 (d, 1H, J=7 Hz), 5.28 (m, 1H), 4.63 (d, 1H, J=17Hz), 3.60 (m, 2H), 3.47 (d, 1H, J=17 Hz), 3.35 (m, 3H), 3.14 (td, 1H,J=5, 13 Hz), 2.75 (m, 5H), 2.42 (m, 1H), 2.23 (m, 1H), 1.90 (m, 4H).##STR39## 1,3-Di-tert-buyloxycarbonyl-tetrahydropyrimidine (5-2)

A heterogeneous mixture of 5-1 (10.0 g, 100 mmol), BOC₂ O (48 g, 220mmol), DMAP (20 mg), and CH₃ CN (500 mL) was heated for 40 hr at 65° C.followed by addition of DMF (100 mL) and then continued heating for 24hr. The cooled reaction mixture was diluted with EtOAc and then washedwith H₂ O, sat. NaHCO₃, 1N HCl, and brine, dried (MgSO₄), andconcentrated. The residue was triturated with hexanes to give 5-2 as ayellow solid.

TLC RF=0.93 (EtOAc); ¹ HNMR (300 MHz, CDCl₃) δ 3.68 (t, J=7 Hz, 4H),2.00 (m, 2H), 1.48 (s, 18 H).

Tert-Butyloxycarbonyl-tetrahydropyrimidine (5-3)

A solution of 5-2 (19.0 g, 63 mmol), Mg(ClO₄)₂ (2.8 g, 12.7 mmol), andCH₃ CN was heated at 50° C. for 2 hr. The cooled solution was dilutedwith CDCl₃ and then washed with 1N HCl, sat. NaHCO₃, and brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 75%EtOAc/hexanes→EtOAc) gave 5-3 as a brown solid.

TLC RF=0.26 (silica, EtOAc); ¹ HNMR (300 MHz, CDCl₃) δ 5.50 (bs, 1H),3.70 (m, 2H), 3.29 (m, 2H), 1.97 (m, 2H), 1.48 (s, 9H).

Tert-Butyloxycarbonyl-2-oxo-3-(3-ethyleneglycolbutyl)-tetrahydropyrimidine (5-4)

To a stirred solution of 5-3 (3.2g, 16.1 mmol) and DMF (50 mL) was addedLiN(TMS)₂ (21 mL, 1M/hexanes). After 20 minutes, the iodide 1-2 (8.6 g,35.2 mmol) in DMF (10 mL) was added and the reaction mixture heated at50° C. for 2 hours. The cooled solution was diluted with CHCl₃ and thenwashed with H₂ O and brine, dried (MgSO₄), and concentrated. Flashchromatography (silica, 60% to 75% EtOAc/hexanes) gave 5-4 as an orangeoil.

TLC RF=0.74 (silica, 70:15:15 CDCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 3.93 (s, 4H), 3.66 (t, J=6Hz, 2H), 3.,44 (m, 2H), 3.30 (m, 2H),1.96 (m, 2H), 1.48 (s, 9H), 1.32 (s, 3H).

1-Oxo-2-(3-ethylene glycol-butyl) tetrahydro-pyrimidine (5-5)

A mixture of 5-4 (3.0 g, 9.5 mmol), TFA (1.5 mL, and toluene (30 mL) wasstirred at ambient temperature for 20 minutes, concentrated and theresidue azeotroped with toluene to remove excess TFA. The residue wasthen dissolved in toluene (30 mL) and treated with NaHCO₃ (3g),filtered, and the filtrate concentrated to give a yellow oil. Flashchromatography (silica, 70:15:15 CHCl₃ /EtOAc/ CH₃ OH) gave 5-5 as ayellow oil.

TLC RF=0.63 (silica, 70:15:15 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 5.16 (bs, 1H), 3.94 (s, 4H), 3.40 (m, 2H), 3.24 (m, 4H), 1.90(m, 2H), 1.34 (s, 3H).

Ethyl 2-oxo-3-[3-ethylene glycol-butyl]tetrahydropyrimidin-1-yl-acetate(5-6)

To a stirred solution of 5-5 (2.0 g, 9.3 mmol) and DMF (50 mL) was addedLiN(TMS)₂ (12.1 mL, 1.0 M/THF). After 20 min, ethyl iodoacetate (1.66mL, 14.0 mmol) was added followed by heating at 60° C. for 1 hr. Thecooled solution was diluted with EtOAc and then washed with H₂ O, sat.NaHCO₃, and brine, dried (MgSO₄), and concentrated. Flash chromatography(silica, 50% to 75% EtOAc/hexanes) gave 5-6 as a colorless oil.

TLC RF=0.72 (silica, 70:15:15 CDCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 4.18 (q, J=7 Hz, 2H), 3.93 (s, 4H), 3.42 (m, 2H), 3.34 (m, 4H),1.98 (m, 2H), 1.92 (m, 2H), 1.34 (s, 3H), 1.25 (t, J=7 Hz, 3H).

Ethyl 2-oxo-3-[3-oxo-butyl]tetrahydro-pyrimidin-1-yl-acetate (5-7)

A solution of 5-6 (750 mg, 2.5 mmol), p-TSA (10 mg), and acetone (30 mL)was refluxed for 1 hr. The cooled solution was diluted with CDCl₃ andthen washed with sat. NaHCO₃ and brine, dried (MgSO₄), and concentratedto give 5-7 as a yellow oil.

TLC RF=0.36 (silica, 10% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 4.17(q, J=7 Hz, 2H), 3.56 (m, 2H), 3.34 (m, 4H), 2.76 (t, J=7 Hz, 2H), 2.17(s, 3H), 2.00 (m, 2H), 1.27 (t, J=7 Hz, 3H).

Ethyl2-oxo-3-[2-naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-l-yl-acetate(5-8)

A mixture of 5-7 (600 mg, 2.3 mmol), 1-4 (343 mg, 2.8 mmol), L-proline(175 mg), and ethanol (25 mL) was heated at reflux for 18 hr. The cooledreaction mixture was concentrated and the residue purified by flashchromatography (silica, 10% CH₃ OH/EtOAc) gave 5-8 as a yellow solid.

TLC RF=0.21 (silica, 10% CH₃ OH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 9.10(m, 1H), 8.19 (m, 1H), 8.14 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.44(m, 1H), 4.18 (q, J=7 Hz, 2H), 3.83 (m, 2H), 3.32 (m, 6H), 1.93 (m, 2H),1.24 (t, J=7 Hz, 3H).

Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridine-2-yl)ethyl]tetrahydropyrimidine-1-yl-acetate (5-9)

A mixture of 5-8 (600 mg, 1.75 mmol), 10% Pd/C (300 mg), and ethanol (10mL) was stirred at ambient temperature under a hydrogen atmosphere (1atm) for 20 hr. The catalyst was removed by filtration through a celitepad and the filtrate concentrated to give 5-9 as a yellow oil.

¹ H NMR (300 MHz, CDCl₃) δ 7.04 (d, J=8 Hz, 1H), 6.42 (d, J=8 Hz, 1H),4.80 (bs, 1H), 4.22-4.03 (m, 4H), 3.60 (m, 2H), 2.78 (m, 2H), 2.66 (m,2H), 1.96 (m, 4H), 1.24 (t, J=7 Hz, 3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthridin-2-yl)tetrahydro-pyrimidin-1-yl-aceticacid (5-10)

A solution of 5-9 (600 mg, 1.73 mmol) and 6N HCl (20 mL) was heated at50° C. for 2 hr. The solution was concentrated followed by azeotropicremoval of H₂ O with CH₃ CN to give 5-10 as a yellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.58 (d, J=8 Hz, 1H), 6.63 (d, J=8 Hz, 1H),3.98 (s, 2H), 3.62 (t, J=7 Hz, 2H), 3.50 (m, 2H), 3.36 (m, 4H), 2.93 (m,2H), 2.80 (m, 2H), 2.00 (m, 4H).

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-1-yl-aceetyl-3(S)-pyridin-3-yl-β-alanine(5-11)

To a stirred solution of 5-10 (250 mg, 0.70 mmol), 1-9 (210 mg, 0.77mmol), EDC (148 mg, 0.77 mmol), HOBT (95 mg, 0.70 mmol), CH₃ CN (2 mL),and DMF (2 mL) was added NMM (542 μL, 4.9 mmol). After stirring atambient temperature for 20 hr, the reaction mixture was diluted withEtOAc and then washed with H₂ O, sat. NaHCO₃, brine, dried (MgSO₄), andconcentrated. Flash chromatography (silica, 70:15:15 CHCl₃ /EtOAc/CH₃OH) gave 5-11 as a colorless oil.

TLC RF=0.31 (silica, 70:15:15 CDCl₃ /EtOAc/CH₃ OH); H NMR (300 MHz,CDCl₃) δ 8.58 (m, 1H), 8.50 (m, 1H), 7.94 (m, 1H), 7.66 (m, 1H), 7.22(m, 1H), 7.05 (d, J=8 Hz, 1H), 6.40 (d, J=8 Hz, 1H), 5.43 (m, 1H), 4.06(q, J=7 Hz, 2H), 4.02 (m, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.39 (m, 2H),3.29 (m, 2H), 3.19 (m, 2H), 2.88 (m, 2H), 2.77 (m, 2H), 2.70 (m, 2H),1.90 (m, 4H), 1.16 (t, J=7 Hz, 3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl}ethyl]-tetrahydropyrimidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine(5-12)

A mixture of 5-11 (100 mg, 0.22 mmol), 1N NaOH (300 μL), and ethanol (1mL) was stirred at ambient temperature for 1 hr, followed byconcentration. Flash chromatography (silica, 25:10:1:1 to 15:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) gave 5-12 as a white solid.

TLC RF=0.22 (silica, 10:10:1:1 EtOAc/ethanol/NH₄ OH, H₂ O); ¹ H NMR (300MHz, CD₃ OD) δ 8.66 (m, 1H), 8.39 (m, 1H), 7.95 (m, 1H), 7.53 (d, J=8Hz, 1H), 7.40 (m, 1H), 6.66 (d, J=8 Hz, 1H), 5.18 (m, 1H), 4.27 (d, J=7Hz, 1H), 4.16 (m, 1H), 3.64 (d, J=7 Hz, 1H), 3.50-3.10 (m, 8H),3.00-2.65 (m, 6H), 1.95 (m, 4H). ##STR40##1,3-Di-tert-buyloxycarbonyl-imidazolidin-2-one (6-2)

A heterogeneous mixture of 6-1 (10.0 g, 116 mmol), BOC₂ O (56 g, 255mmol), DMAP (20 mg), and CH₃ CN (400 mL) was heated for 18 hr at 60° C.The cooled reaction mixture was diluted with EtOAc and then washed withH₂ O, sat. NaHCO₃, 1N HCl, and brine, dried (MgSO₄), and concentrated.The residue was triturated with hexanes to give 6-2 as a white solid.

TLC RF=0.91 (EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 3.73 (s, 4H), 1.53 (s,18 H).

Tert-Butyloxycarbonyl-imidazolidin-2-one (6-3)

A solution of 6-2 (28.0 g, 98 mmol), Mg(CIO₄)₂ (4.3 g, 20 mmol), and CH₃CN (400 mL) was heated at 50° C. for 3 hr. The cooled solution wasdiluted with CHCl₃ and then washed with 1N HCl, sat. naHCO₃, and brine,dried (Mg S₄), and concentrated. Flash chromatography (silica, 50%EtOAc/hexanes→EtOAc) gave 6-3 as a yellow solid.

TLC RF=0.31 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 6.27 (bs, 1H),3.86 (m, 2H), 3.47 (m, 2H), 1.50 (s, 9H).

1-Tert-Butyloxycarbonyl-3-(3-ethylene glycol-butyl)imidazolidin-2-one(6-4)

To a stirred solution of 6-3 (4.5 g, 24 mmol) and DMF (50 mL) was addedLiN(TMS)₂ (26.6 mL, 1M/hexanes). After 20 minutes, the iodide 1-2 (8.6g, 35.2 mmol) in DMF (10 mL) was added and the reaction mixture heatedat 60° C. for 4 hours. The cooled solution was diluted with CHCl₃ andthen washed with H₂ O and brine, dried (MgSO₄), and concentrated. Flashchromatography (silica, 75% EtOAc/hexanes) gave 6-4 as an yellow solid.

TLC RF=0.71 (silica, 70:15:15 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 3.93 (s, 4H), 3.75 (m, 2H), 3.36 (m, 4H), 1.90 (m, 2H), 1.53(s, 9H), 1.34 (s, 3H).

1-(3-Ethylene glycol-butyl)imidazolidin-2-one (6-5)

A mixture of 6-4 (4.0 g, 13.3 mmol), TFA (3 mL, and toluene (60 mL) wasstirred at 50° C. for 60 minutes, concentrated and the residueazeotroped with toluene to remove excess TFA. The residue was thendissolved in toluene (30 mL) and treated with NaHCO₃ (3g), filtered, andthe filtrate concentrated to give a yellow oil. Flash chromatography(silica, 70:25:5 CDCl₃ /EtOAc/CH₃ OH) gave 6-5 as a white solid.

TLC RF=0.58 (silica, 70:15:15 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 4.25 (bs, 1H), 3.94 (s, 4H), 3.44 (m, 4H), 3.32 (m, 2H), 1.90(m, 2H), 1.35 (s, 3H).

Ethyl 2-oxo-3-[3-ethylene glycol-butyl]imidazolidin-1-yl-acetate (6-6)

To a stirred solution of 6-5 (2.0 g, 10 mmol) and DMF (50 mL) was addedLiN(TMS)₂ (11 mL, 1.0 M/THF). After 20 min, ethyl iodoacetate (3.5 mL,30 mmol) was added at ambient temperature. After 3 hr the solution wasdiluted with EtOAc and then washed with H₂ O, sat. NaHCO₃, and brine,dried (MgSO₄), and concentrated. Flash chromatography (silica, 50% to75% EtOAc/hexanes) gave 6-6 as a colorless oil.

TLC RF=0.71 (silica, 70:15:15 CDCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 4.18 (q, J=7 Hz, 2H), 3.93 (s, 4H), 3.91 (m, 2H), 3.50-3.30 (m,6H), 1.90 (m, 2H), 1.92 (m, 2H), 1.35 (s, 3H), 1.25 (t, J=7 Hz, 3H).

Ethyl 2-oxo-3-[3-oxo-butyl]imidazolidin-1-yl-acetate (6-7)

A solution of 6-6 (1.4 g, 4.9 mmol), p-TSA (10 mg), and acetone (30 mL)was refluxed for 1 hr. The cooled solution was diluted with CHCl₃ andthen washed with sat. NaHCO₃ and brine, dried (MgSO₄), and concentratedto give 6-7 as a yellow oil.

TLC RF=0.34 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 4.17 (q, J=7 Hz,2H), 3.94 (s, 2H), 3.48 (m, 2H), 3.42 (m, 4H), 2.72 (t, J=7 Hz, 2H),2.17 (s, 3H), 1.27 (t, J=7 Hz, 3H).

Ethyl 2-oxo-3-[2-naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetate (6-8)

A mixture of 6-7 (1.0 g, 4.1 mmol), 1-4 (604 mg, 4.9 mmol), L-proline(238 mg), and ethanol (50 mL) was heated at reflux for 20 hr. The cooledreaction mixture was concentrated and the residue purified by flashchromatography (silica, 70:25:5 CDCl₃ /EtOAc/CH₃ OH) gave 6-8 as ayellow oil.

TLC RF=0.42 (silica, 70:15:15 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 9.10 (m, 1H), 8.19 (m, 1H), 8.14 (d, J=8 Hz, 1H), 7.52 (d, J=8Hz, 1H), 7.44 (m, 1H), 4.17 (q, J=7 Hz, 2H), 3.81 (m, 2H), 3.42 (m, 4H),3.32 (m, 4H), 1.24 (t, J=7 Hz, 3H).

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridine-2-yl)ethyl]imidazolidin-1-yl-acetate(6-9)

A mixture of 6-8 (1.1 g, 3.35 mmol), 10% Pd/C (500 mg), and ethanol (30mL) was stirred at ambient temperature under a hydrogen atmosphere (1atm) for 20 hr. The catalyst was removed by filtration through a celitepad and the filtrate concentrated to give 6-9 as a colorless oil.

TLC RF=0.11 (silica, 70:25:5 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 7.04 (d, J=8 Hz, 1H), 6.42 (d, J=8 Hz, 1H), 4.80 (bs, 1H),4.22-4.03 (m, 4H), 3.96 (s, 2H), 3.55 (m, 2H), 3.40 (m, 2H), 2.78 (m,2H), 2.68 (m, 2H), 1.90 (m, 2H), 1.24 (t, J=7 Hz, 3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthridin-2-yl)imidazolidin-1-yl-aceticacid (6-10)

A solution of 6-9 (1.0 g, 3.0 mmol) and 6N HCl (40 mL) was heated at 60°C. for 1 hr. The solution was concentrated followed by azeotropicremoval of H₂ O with CH₃ CN to give 6-10 as a yellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.58 (d, J=8 Hz, 1H), 6.63 (d, J=8 Hz, 1H),3.98 (s, 2H), 3.50 (m, 4H), 3.36 (m, 4H), 2.93 (m, 2H), 2.82 (m, 2H),1.97 (m, 4H).

Ethyl2-oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine(6-11)

To a stirred solution of 6-10 (240 mg, 0.70 mmol), 1-9 (207 mg, 0.77mmol), EDC (269 mg, 1.4 mmol), HOBT (95 mg, 0.70 mmol), and CH₃ CN (3mL) was added NMM (619 μL, 5.6 mmol). After stirring at ambienttemperature for 20 hr, the reaction mixture was diluted with EtOAc andthen washed with H₂ O, sat. NaHCO₃, brine, dried (MgSO₄), andconcentrated. Flash chromatography (silica, 70:15:15 CHCl₃ /EtOAc/CH₃OH) gave 6-11 as a colorless oil.

TLC RF=0.41 (silica, 70:15:15 CDCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 8.58 (m, 1H), 8.50 (m, 1H), 7.94 (m, 1H), 7.66 (m, 1H), 7.22(m, 1H), 7.05 (d, J=8 Hz, 1H), 6.40 (d, J=8 Hz, 1H), 5.43 (m, 1H), 4.06(q, J=7 Hz, 2H), 3.85 (m, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 3.33 (m, 4H),2.90 (m, 2H), 2.77 (m, 2H), 2.70 (m, 2H), 1.90 (m, 2H), 1.77 (m, 2H),1.18 (t, J=7 Hz, 3H).

2-Oxo-3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine(6-12)

A mixture of 6-11 (160 mg, 0.33 mmol), 1N NaOH (500 μL), and ethanol (1mL) was stirred at ambient temperature for 1 hr, followed byconcentration. Flash chromatography (silica, 25:10:1:1 to 15:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) gave 6-12 as a white solid.

TLC RF=0.21 (silica, 10:10:1:1 EtOAc/ethanol/NH₄ OH, H₂ O); ¹ H NMR (300MHz, CD₃ OD) δ 8.66 (m, 1H), 8.39 (m, 1H), 7.95 (m, 1H), 7.53 (d, J=8Hz, 1H), 7.40 (m, 1H), 6.66 (d, J=8 Hz, 1H), 5.22 (m, 1H), 3.93 (d, J=17Hz, 1H), 3.74 (d, J=17 Hz, 1H), 4.00-3.20 (m, 9H), 3.00-2.65 (m, 6H),1.89 (m, 4H). ##STR41## Ethyl2-oxo-3(R)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine(7-2)

To a stirred solution of 4-1 (175 mg, 0.52 mmol), 7-1 (214 mg, 0.72mmol; for preparation see U.S. Pat. No. 5,321,034), EDC (197 mg, 1.0mmol), HOBT (70 mg, 0.52 mmol), and CH₃ CN (3 mL) was added NMM (498 μL,4.1 mmol). After stirring at ambient temperature for 20 hr, the reactionmixture was diluted with EtOAc and then washed with H₂ O, sat. NaHCO₃,brine, dried (MgSO₄), and concentrated. Flash chromatography (silica,70:25:5 CHCl₃ /EtOAc/CH₃ OH) gave 7-2 as a white solid.

TLC RF=0.11 (silica, 70:25:5 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 8.29 (bs, 1H), 7.55 (d, J=7 Hz, 1H), 7.36 (d, J=7 Hz, 1H),7.20-7.00 (m, 3H), 6.63 (d, J=7 Hz, 1H), 6.39 (d, J=7 Hz, 1H), 4.30 (m,1H), 4.10 (q, J=7 Hz, 2H), 3.94 (d, J=17 Hz, 1H), 3.83 (d, J=17 Hz, 1H),3.36 (m, 4H), 2.80 (m, 2H), 2.69 (m, 3H), 2.53 (d, J=6 Hz, 2H), 2.50 (m,1H), 2.24 (m, 2H), 1.93 (m, 4H), 1.75 (m, 2H), 1.18 (t, J=7 Hz, 3H).

2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine(7-3)

A mixture of 7-2 (60 mg, 0.11 mmol), 1N NaOH (132 μL), and ethanol (1mL) was stirred at ambient temperature for 1 hr, followed byconcentration. Flash chromatography (silica, 25:10:1:1 to 15:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) gave 7-3 as a white solid.

TLC RF=0.12 (silica, 10:10:1:1 EtOAc/ethanol/NH₄ OH/H₂ O); ¹ H NMR (300MHz, CD₃ OD) β 7.52 (d, J=7 Hz, 1H), 7.43 (d, J=7 Hz, 1H), 7.30 (d, J=8Hz, 1H), 7.05 (m, 2H), 6.92 (m, 1H), 6.48 (d, J=7 Hz, 1H), 4.54 (d, J=17Hz, 1H), 4.27 (m, 1H), 3.50-1.70 (m, 22H). ##STR42##N-(4-Iodo-phenylsulfonylamino)-L-asparagine (8-2)

To a stirred solution of acid 8-1 (4.39 g, 33.2 mmol), NaOH (1.49 g,37.2 mmol), dioxane (30 ml) and H₂ O (30 ml) at 0° C. was added pipsylchloride (10.34 g, 34.2 mmol). After ˜5 minutes, NaOH (1.49, 37.2 mmol)dissolved in 15 ml H₂ O, was added followed by the removal of thecooling bath. After 2.0 h, the reaction mixture was concentrated. Theresidue was dissolved in H₂ O (300 ml) and then washed with EtOAc. Theaqueous portion was cooled to 0° C. and then acidified with concentratedHCl. The solid was collected and then washed with Et₂ O to provide acid8-2 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 7.86 (d, 2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz)3.70 (m, 1H), 2.39 (m, 2H).

2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (8-3)

To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H₂ O (40 ml) at0° C. was added Br₂ (1.30 ml, 24.9 mmol) dropwise over a ten minuteperiod. After ˜5 minutes, acid 8-2 (9.9 g, 24.9 mmol), NaOH (2.00 g,49.8 mmol) and H₂ O (35 ml) were combined, cooled to 0° C. and thenadded in a single portion to the reaction. After stirring for 20 minutesat 0° C., the reaction was heated to 90° C. for 30 minutes and thenrecooled to 0° C. The pH was adjusted to ˜7 by dropwise addition ofconcentrated HCl. The solid was collected, washed with EtOAc, and thendried in vacuo to provide acid 8-3 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 8.02 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz),4.36 (m, 1H), 3.51 (dd, 1H, J=5 Hz, 13 Hz) 3.21 (m, 1H).

Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hydrochloride (8-4)

HCl gas was rapidly bubbled through a suspension of acid 8-3 (4.0 g,10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bathwas removed and the reaction was heated to 60° C. After 18 h, thereaction was concentrated to provide ester 8-4 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.98 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz),4.25 (q, 1H, J=5 Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t,3H, J=7 Hz).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoate (8-5)

A mixture of ester 8-5a (700 mg, 2.63 mmol), (for preparation, see:Scheme 29 of PCT International Application Publication No. WO 95/32710,published Dec. 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1atm H₂. After 20 h, the reaction was filtered through a celite pad andthen concentrated to provide ester 8-5 as a brown oil.

TLC R_(f) =0.23 (silica, 40% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.95 (d, 2H, J=8 Hz), 7.26 (m, 3H), 6.43 (d, 1H, J=7 Hz), 6.35 (d, 1H,J=8 Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J=7 Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoic acid hydrochloride (8-6)

A suspension of ester 8-5 (625 mg, 2.31 mmol) in 6N HCl (12 ml) washeated to 60° C. After ˜20 h, the reaction was concentrated to give acid8-6 as a tan solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.96 (d, 2H, J=8 Hz), 7.80 (m, 1H), 7.33 (d,2H, J=8 Hz), 6.84 (d, 1H, J=9 Hz), 6.69 (d, 1H, J=7 Hz), 3.09 (m, 4H).

Ethyl4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenylsulfonylamino)-.beta.-alanine(8-7)

A solution of acid 8-6 (400 mg, 1.43 mmol), amine 8-4 (686 mg, 1.57mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 μl,5.72 mmol) and DMF (10 ml) was stirred for ˜20 h. The reaction wasdiluted with EtOAc and then washed with sat NaHCO₃, brine, dried (MgSO₄)and concentrated. Flash chromatography (silica, EtOAC→5%isopropanol/EtOAc) provided amide 8-7 as a white solid.

TLC R_(f) =0.4 (silica, 10% isopropanol/EtOAc); ¹ H NMR (300 MHz, CD₃OD) δ 7.79 (d, 2H, J=9 Hz) 7.61 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=9 Hz),7.29 (m, 1H), 7.27 (d, 2H, J=8 Hz), 4.20 (m, 1H), 3.95 (q, 2H, J=7 Hz),3.66 (dd, 1H, J=6 Hz, 14 Hz), 3.49 (dd, 1H, J=8 Hz, 13 Hz), 3.01 (m,2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7 Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenylsulfonylamino)-.beta.-alanine(8-8)

A solution of ester 8-7 (200 mg, 0.3213 mmol) and 6N HCl (30 ml) washeated to 60° C. After ˜20 h, the reaction mixture was concentrated.Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O) providedacid 8-8 as a white solid.

TLC R_(f) =0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O); ¹ H NMR (400MHz, DMSO) δ 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H, J=8 Hz), 7.62 (d,2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz), 7.27 (m, 3H), 6.34 (d, 1H, J=7 Hz),6.25 (d, 1H, J=8 Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H), 2.97(m, 2H), 2.79 (m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl-phenylsulfonylamino-β-alanine(8-9)

A solution of iodide 8-8 (70 mg, 0.1178 mmol), (CH₃ Sn)₂ (49 μl, 0.2356mmol), Pd(PPh₃)₄ (5 mg) and dioxane (7 ml) was heated to 90° C. After 2h, the reaction was concentrated and then purified by prep HPLC(Delta-Pak C₁₈ 15 μM 100A°, 40×100 mm; 95:5→5:95 H₂ O/CH₃ CN) providedthe trifluoroacetate salt. The salt was suspended in H₂ O (10 ml),treated with NH₄ OH (5 drops),and then lyophilized to provide amide 8-9as a white solid.

¹ H NMR (400 MHz, DMSO) δ 8.40 (m, 1H), 8.18 (d, 1H, J=8 Hz), 7.67 (m,5H), 7.56 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz), 6.95-7.52 (m, 2H), 6.45(bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.86(m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-¹²⁵iodophenylsulfonylamino-β-alanine (8-10)

An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na¹²⁵ I(Amersham, IMS30) and stirred for five minutes at room temperature. Asolution of 0.1 mg of 8-9 in 0.05 mL of 10% H₂ SO₄ /MeOH was made andimmediately added to the Na¹²⁵ I/iodobead vial. After stirring for threeminutes at room temperature, approximately 0.04-0.05 mL of NH₄ OH wasadded so the reaction mixture was at pH 6-7. The entire reaction mixturewas injected onto the HPLC for purification [Vydac peptide-protein C-18column, 4.6×250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H₂ O(0.1% TFA) to 90% acetonitrile (0.1% TFA):H₂ O (0.1% TFA) over 30minutes, 1 mL/min]. The retention time of 8-10 is 17 minutes under theseconditions. Fractions containing the majority of the radioactivity werepooled, lyophilized and diluted with ethanol to give approximately 1 mCiof 8-10, which coeluted on HPLC analysis with an authentic sample of8-8.

Instrumentation: Analytical and preparative HPLC was carried out using aWaters 600E Powerline Multi Solvent Delivery System with 0.1 mL headswith a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detectorwith a Gilson FC203 Microfraction collector. For analytical andpreparative HPLC a Vydac peptide-protein C-18 column, 4.6×250 mm wasused with a C-18 Brownlee modular guard column. The acetonitrile usedfor the HPLC analyses was Fisher Optima grade. The HPLC radiodetectorused was a Beckman 170 Radioisotope detector. A Vydac C-18 protein andpeptide column, 3.9×250 mm was used for analytical and preparative HPLC.Solutions of radioactivity were concentrated using a Speedvac vacuumcentrifuge. Calibration curves and chemical concentrations weredetermined using a Hewlett Packard Model 8452A UV/Vis Diode ArraySpectrophotometer. Sample radioactivities were determined in a PackardA5530 gamma counter. ##STR43## Methyl(S)-(3-amino-2-oxo-pyrrolidin-1-yl)-acetic acid hydrochloride(9-2)

A solution of 9-1 (0.50 g, 1.84 mmol) (prepared as described byFreidinger, R. M.; Perlow, D. S.; Veber, D. F.; J. Org. Chem., 1982, 26,104) in anhydrous ethyl acetate (50 mL) was cooled to 0° C. andsaturated with HCl gas, then stirred at 0° C. for 2 h. The resultingcolorless solution was concentrated at reduced pressure and the residuetriturated with anhydrous diethyl ether giving 9-2 as a hygroscopicwhite solid.

¹ H NMR (300 MHz, CD₃ OD) δ 4.16 (d, 2H); 4.2 (m, 1H); 3.68 (s, 3H);3.53 (m, 2H); 2.58 (m, 1H); 2.09 (m, 1H).

Methyl2-oxo-3(S)-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl]-aceticacid (9-4)

A solution of 9-2 (232 mg, 1.11 mmol) and 9-3 (176 mg, 1.11 mmol)(prepared as reported by Weissenfels, M.; Ulrici, B.; Z. Chem. 1978, 18,20.) in anhydrous methanol (10 mL) was treated with NaOAc (91 mg, 1.11mmol), NaBH₃ CN (70 mg, 1.11 mmol) and powdered 4 Å molecular sieves(450 mg). The resulting mixture was stirred at 0° for 3.5 h, thenconcentrated and the residue subjected to flash chromatography on silicagel (95:4.5:0.5 CH₂ Cl₂ /MeOH/NH₄ OH) to afford 9-4 as a colorlessglass.

FAB MS (315, M⁺¹); ¹ H NMR (300 MHz, CD₃ OD) δ 9.04 (d, 1H); 8.41 (dd,1H); 8.38(d, 1H); 7.72 (d, 1H); 7.62 (dd, 1H); 4.31 (d, 2H); 4.21 (m,2H); 3.68 (s, 3H);3.63 (m, 1H); 3.53 (m, 2H); 2.52 (m, 1H); 1.95 (m,1H).

Methyl[3(S)-[tert-butoxycarbonyl-[1,8]naphthyridin-2-ylmethyl)-amino]-2-oxo-pyrrolidin-1-yl]-aceticacid (9-5)

A solution of amine 9-4 (69 mg, 0.22 mmol) in THF (5 mL) was treatedwith Boc₂ O (83 mg, 0.24 mmol) and stirred at room temperature for 18 h.The solvent was removed in vacuo and the resulting residue isolated bychromatography on silica gel (5% MeOH/CH₂ Cl₂) to afford 9-5 as a yellowglass. FAB MS (415, M⁺¹);

¹ H NMR (300 MHz, CD₃ OD) δ 9.04 (d, 1H); 8.20 (m, 2H); 7.88 (d, 0.5H(rotamer a)); 7.82 (d, 0.5H (rotamer b)); 7.46(m, 1H); 5.1-4.3 (m, 5H);3.81 (m, 2H); 3.72 (s, 3H); 3.41 (m, 2H); 2.36 (m, 2H); 1.47 (s, 4.5 H(rotamer a)); 1.30 (s, 4.5 H , (rotamer b)).

Methyl[3(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-aminol-]2-oxo-pyrrolidin-1-yl]-aceticacid (9-6)

A solution of 9-5 (40 mg, 0.097mmol) in EtOH (5 mL) was treated with 10%Pd on C (8 mg) and then stirred under a H₂ filled balloon for 16 h. Thecatalyst was removed by filtration through celite and the filtrateconcentrated to afford 9-6 as a colorless glass.

¹ H NMR (300 MHz, CD₃ OD) δ 7.10 (d, 1H) 6.78 (d, 0.5H (rotamer a));6.62 (d, 0.5H (rotamer b)); 4.8-3.9 (m, 5H); 3.81 (m, 2H); 3.72 (s, 3H);3.38 (m, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H (rotamer a)); 1.15 (s, 4.5 H.(rotamer b)).

3(S)-[tert-butoxycarbonyl-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-aminol-2-oxo-pyrrolidin-1-yl]-aceticacid (9-7)

A solution of 9-6 (38 mg, 0.091 mmol) in 50% aqueous THF (2 mL) wastreated with 1.0 N NaOH (95 mL, 0.095 mmol) and stirred at roomtemperature for 2 h. The reaction was nuetralized with 1N HCl,evaporated, and the residue dissolved in MeOH (2.5 mL), filtered andevaporated to afford 9-7 as a colorless glass.

¹ H NMR (300 MHz, CD₃ OD) δ 7.31 (d, 1H) 6.78 (br, d, 1H); 4.8-3.9 (m,5H); 3.81 (m, 2H); 3.38 (m, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H (rotamera)); 1.15 (s, 4.5 H , (rotamer b)).

Ethyl3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionicacid (9-8)

9-7 (43 mg, 0.093 mmol), 1-9 (25 mg, 0093 mmol), EDC (18 mg, 0.093mmol), HOBT (13 mg, 0.093 mmol), and N-methyl morpholine (31 mL, 0.28mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 18 h,then concentrated in vacuuo and the residue chromatographed on silicagel using 5% MeOH/CH₂ Cl₂ as eluent affording 9-8 as a colorless glass.

¹ H NMR (300 MHz, CDCl₃) δ 8.61 (s, 1H); 8.45 (d, 1H); 8.00 (m, 1H);7.68, (d, 1H); 7.21 (m, 1H); 7.17 (d, 1H); 5.56 (m, 1H); 4.75 (s, 2H);4.45 (m, 2H); 4.05 (q, 2H); 3.95 (m, 1H); 3.5-3.3 (m, 4H); 2.92 (m, 1H);2.87 (m, 1H); 2.74 (m, 2H); 2.35 (m, 2H); 1.92 (m, 2H); 1.36 (s, 9H);1.21 (t, 3H).

3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid (9-9)

9-8 (25 mg, 0.043 mmol) was dissolved in 6 N HCl (2 mL) and stirred atroom temperature for 16 h, then evaporated to afford 9--9 as a paleyellow solid.

FAB MS (453, M⁺¹); ¹ H NMR (300 MHz, CD₃ OD) δ 9.00 (s, 1H); 8.81 (d,1H); 8.79(m, 1H); 8.10 (m, 1H); 7.71 (d, 1H); 7.01 (m, 1H); 5.56 (m,1H); 4.75 (s, 2H); 4.61 (m, 1H); 4.50 (m, 1H); 4.35 (m, 1H); 4.10 (s,2H); 3.62 (m, 4H); 3.4-3.0 (m, 2H); 2.8 (m, 2H); 2.70 (m, 1H); 2.45 (m1H); 1.98 (m, 2H).

Following the procedure described in Scheme 10, bicyclic compounds suchas 10-6 are readily prepared by one of ordinary skill in the art.##STR44## 3(R)-phenyl-tetrahydro-pyrrolo[1,2(S)-c]oxazol-5-one (11-2)

A mixture of alcohol (S)-5-(hydroxymethyl)-2-pyrrolidinone (11-1, Fluka)(5.0 g, 43.4 mmol), benzaldehyde (5.7 mL, 56.4 mmol), p-TSA (80 mg,0.4340 mmol) and toluene (125 mL) was heated to reflux with azeotropicremoval of water for 18 hours. The solution was concentrated. Flashchromatography (silica, 50% EtOAc/hexanes) gave 11-2 as a yellow oil.

TLC R_(f) =0.21 (silica,50% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.29→7.46 (m, 5H), 6.34 (s, 1H), 4.24 (m, 1H), 4.16 (t, J=5.8 Hz, 1H),3.49 ((t, J=7.8 Hz, 1H), 2.82 (m, 1H), 2.55 (m, 1H), 2.39 (m,1H), 1.97(m,1H).

6(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-3(R)-phenyl-tetrahydropyrrolo[1,2(S)-c]oxazol-5-one(11-3)

To a stirred solution of 11-2 (7.0 g, 34.4 mmol), HMPA (30.0 mL, 172mmol) and THF (150 mL) at -78° C. was added LDA (18.9 mL, 37.8 mmol,2.0M in heptane/THF). After 10 minutes, the reaction was warmed to -15°C. After 20 min, 1-2 (8.3 g, 34.4 mmol), dissolved in 10 mL of THF, wasadded. After 2 h, the reaction was warmed to ambient temperature for 3.0hours and then recooled to -15° C. for 18 hours. The reaction was warmedto ambient temperature for 2 hours and then diluted with Et₂ O, washedwith H₂ O, dried (MgSO₄) and concentrated. Flash chromatography (silica,40%→60% EtOAc/hexanes) gave 11-3 as an oil.

TLC R_(f) =0.28 (silica, 50% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.25→7.46 (m, 5H), 6.33 (s,1H), 4.24 (m, 1H), 4.11 (m, 1H), 3.95 (s,4H), 3.52 (t, J=7.3 Hz, 1H), 2.87 (m, 1H), 2.57 (m, 1H), 2.10 (m,1H)1.40→1.86 (m, 4H), 1.34 (s,3H).

1-benzyl-5(S)-hydroxymethyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)ethyl]-pyrrolidin-2-one(11-4)

A mixture of 11-3 (2.0 g, 6.30 mmol) and 10% Pd/carbon (2.0 g) in EtOH(30 mL) was stirred under a balloon of hydrogen for 1.0 h. Followingfiltration and evaporative removal of the solvent, the residue dissolvedin benzene (30 mL), treated with TsOH (10 mg) and ethylene glycol (1.05mL, 18.9 mmol) and then heated to reflux with azeotropic removal ofwater for 1 hour. The reaction was concentrated. Flash chromatography(silica, 70:23:7 CHCl₃ /EtOAc/MeOH) gave 11-4 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ 7.30 (m, 5H), 4.64 (d, J=15 Hz, 1H), 4.25 (d,J=15 Hz, 1H), 3.95 (s, 4H), 3.72 (m, 1H), 3.49 (m, 2H), 2.46 (m, 1H),2.15 (m, 2H), 1.74 (m,2H), 1.53 (m,2H) 1.35 (s,3H).

1-benzyl-5(S)-iodomethyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(11-5)

To a stirred solution of 11-4 (2.0 g, 6.26 mmol), PPh₃ (2.63 g, 10.0mmol), imidazole (725 mg, 10.6 mmol) and CH₃ CN (30 mL) at 0° C. wasadded I₂ (2.39 g, 9.39 mmol) in five portions over 15 minutes. After 20minutes, the reaction was warmed to 50° C. for 30 minutes and thenpoured into 200 mL 1:1 EtOAc/hexanes. The solution was washed with 10%sodium bisulfite, sat NaHCO₃, brine, dried (MgSO₄) and concentrated.Flash chromatography (silica, 40% EtOAc/hexanes) gave 11-5 as an oil.

TLC R_(f) =0.27 (silica, 50% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.19→7.35 (m, 5H), 5.04 (d, J=15.1 Hz, 1H), 3.96 (m, 5H), 3.30 (m 1H),3.19 (m, 2H), 2.50 (m, 1H), 2.32 (m,1H), 2.12 (m,1H), 1.79 (m,2H), 1.58(m,1H), 1.36 (m,4H).

1-benzyl-5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(11-6)

To a stirred solution of 11-5 (900 mg, 6.26 mmol) and HMPA (30 mL) wasadded NaBH₄ (156 mg, 4.20 mmol). After 45 minutes, the reaction waspoured into 50 mL 1:1 Et₂ O/hexanes and then washed with H₂ O, brine,dried (MgSO₄) and concentrated to provide 11-6 as an oil.

TLC R_(f) =0.34 (silica, 50% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.20→7.33 (m, 5H), 4.95 (d, J=15.1 Hz, 1H),4.03 (d, J=14.9 Hz, 1H), 3.95(s 4H), 3.41 (m, 1H), 2.38 (m, 2H), 2.10 (m,1H), 1.75 (m,2H), 1.48(m,1H), 1.35 (s,3H), 1.16 (m,4H).

5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(11-7)

Into a 3-necked 500 mL flask at -78° C. was condensed 200 mL of ammonia.Lithium (64 mg, 9.25 mmol) was washed with MeOH, then THF and then addedto the ammonia. After 20 minutes, 11-6 (560 mg, 1.85 mmol), dissolved in25 mL of THF, was added. After 30 minutes, the reaction was quenchedwith NH₄ Cl; 200 mL of THF was added, the cooling bath was removed andthe solution purged with argon for 30 minutes to remove the ammonia. Thesolution was dried (MgSO₄) and concentrated. Flash chromatography(silica, EtOAc→5% MeOH/EtOAc) gave 11-7 as an oil.

TLC R_(f) =0.33 (silica, 10% MeOH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ5.98 (br s, 1H), 3.94 (s, 4H), 3.67 (m 1H), 2.40 (m, 2H), 2.02 (m, 1H),1.70 (m,2H), 1.40 (m,1H), 1.33 (s,3H), 1.22 (m,4H).

{5(R)-methyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-2-oxo-pyrrolidin-1-yl}-aceticacid ethyl ester (11-8)

To a stirred solution of 11-7 (355 mg, 1.67 mmol) and THF (10 mL) at-78° C. was added NaN(TMS)₂ (1.83 mL, 1.83 mmol, 1.0M in THF). After 20min, ethyl bromoacetate (0.203 mL, 1.84 mmol) was added and the reactionwas warmed to 0° C. After 30 minutes, the reaction mixture was dilutedwith EtOAc and then washed with H₂ O, brine, dried (MgSO₄), andconcentrated to give 11-8 as a yellow oil.

TLC R_(f) =0.90 (silica, 10% MeOH/EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ4.35 (d, J=17.6 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.94 (s, 4H), 3.74 (m,3H), 2.44 (m, 2H), 2.05 (m, 1H), 1.73 (m, 2H), 1.43 (m, 1H), 1.33(s,3H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H).

[5(R)-methyl-2-oxo-3(S)-(3-oxo-butyl)-pyrrolidin-1-yl]-acetic acid ethylester (11-9)

A solution of 11-10 (360 mg, 1.20 mmol), p-TSA (10 mg) and acetone (20mL) was heated at reflux for 1 hr. The cooled reaction mixture wasdiluted with EtOAc and then washed with sat. NaHCO₃ and brine, dried(MgSO₄), and concentrated to afford 11-9 as an oil.

TLC R_(f) =0.54 (silica, 75% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ4.32 (d, J=17.6 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (m, 3H), 2.72 (m,2H), 2.42 (m, 1H), 2.16 (s, 3H), 1.99 (m, 1H), 1.78 (m, 1H), 1.27 (t,J=7.1 Hz, 3H), 1.20 (d, J=6.1 Hz, 3H).

[5(R)-methyl-3(S)-(2-[1,8]naphthyridin-2-yl-ethyl)-2-oxo-pyrrolidin-1-yl]-aceticacid ethyl ester (11-10)

A mixture of 11-9 (220 mg, 0.8619 mmol), 1-4, 2-amino-3-formylpyridine(137 mg, 1.12 mmol) and proline (99 mg, 0.8619 mmol) in absolute ethanol(5 mL) was heated at reflux for 12 h. Following evaporative removal ofthe solvent, the residue was chromatographed (silica gel, 70:25:5chloroform/ethyl acetate/MeOH) to give 11-10 as a yellow oil.

TLC Rf=0.37 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 9.08 (m, 1H), 8.16 (dd, J=2 Hz, 6 Hz 1H), 8.12 (d,J=8 Hz, 1H),7.46 (m, 2H), 4.33 (d, J=17.5 Hz, 1H), 4.17 (m, 2H), 3.71 (m, 3H), 3.21(t, J=8.0 Hz, 2H), 2.54 (m, 2H), 2.39 (m, 1H), 2.02 (m, 1H), 1.35 (m,1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (d, J=6.3 Hz, 3H).

{5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-aceticacid ethyl ester (11-11)

A mixture of 1-10 (250 mg, 0.7323 mmol) and 10% Pd/carbon (250 mg) inEtOH (5 mL) was stirred under a balloon of hydrogen for 20 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH togive 11-11 as a colorless oil.

TLC Rf=0.25 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 7.05 (d, 1H, J=7.3 Hz), 6.39 (d, 1H, J=7.3 Hz), 4.77 (br s,1H), 4.17 (d, 1H, J=17.5 Hz), 4.15 (m, 2H), 3.71 (m, 2H), 3.39 (m, 2H),2.64 (m, 4H), 2.46 (m, 2H), 2.30 (m, 1H), 1.91 (m, 2H), 1.88 (m, 1H),1.26(t, 3H, J=6.1 Hz) 1.23 (m,1H), 1.19 (d, J=6.4 Hz, 3H).

{5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-aceticacid hydrochloride (11-12)

A mixture of 11-11 (185 mg, 0.5356 mmol) and 6N HCl (10 mL) was heatedat 60° C. for 1 h. Evaporative removal of the solvent gave 11-12 as ayellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.59 (d, 1H, J=7.3 Hz), 6.66 (d, 1H, J=7.3Hz), 4.17 (d, 12H, J=17.8, Hz), 3.90 (d, 1H, J=17.8, Hz), 3.77 (m, 1H),3.50 (t, J=5.4 Hz, 2H), 3.31 (m, 4H), 2.52 (m, 2H), 2.25 (m, 1H), 1.95(t, 2H, J=6.6 Hz), 1.80 (m, 1H), 1.34 (m, 1H), 1.25 (d, J=6.3 Hz, 3H)

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester (11-13)

A mixture of 11-12 (350 mg, 0.9892 mmol), 2-9 (193 mg, 1.09 mmol), EDC(378 mg, 1.98 mmol), HOBT (134 mg, 0.9892 mmol) and NMM (1.10 mL, 7.91mmol) in CH₃ CN (5 mL) was stirred for 20 h. The mixture was dilutedwith ethyl acetate, washed with sat. NaHCO₃, brine, and dried overMgSO₄. Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH togive 11-13 as a colorless foam.

TLC Rf=0.15 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 7.05 (m, 2H), 6.39 (d, 1H, J=7.3 Hz), 5.04 (m, 1H), 4.16 (q,2H, J=7.1 Hz), 3.90 (s, 2H), 3.64 (m, 1H),3.39 (m, 2H), 2.69 (m, 6H),2.47 (m, 2H), 2.30 (m, 1H), 1.90 (m, 2H), 1.64 (m, 2H), 1.20 (m, 7H).

2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine(11-14)

To a solution of 11-13 (70 mg, 0.1589 mmol) in EtOH (1 mL) was added 1NNaOH (0.175 ml, 0.164 mmol). After stirring for 1 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 25:10:1:1 to15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH to give 11-14 as a colorlessfoam.

TLC Rf=0.21 (10:10:1:1 ethyl acetate/EtOH/water/NH₄ OH). ¹ H NMR (300MHz, CD₃ OD) δ 7.42 (d, 1H, J=7.3 Hz), 6.49 (d, 1H, J=7.3 Hz), 4.35(d,J=17.1 Hz, 1H), 3.64 (m, 1H,), 3.50 (m, 3H,), 3.18 (m, 2H), 2.77 (t,J=5.6 Hz, 2H), 2.55 (m, 5H), 2.23 (m, 1H), 1.91 (m, 4H), 1.41 (m, 1H)1.28 (d, J=6.3 Hz, 3H). ##STR45##1-benzyl-5(S)-methyl-p-toluenesulfonate-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(12-1)

To a stirred solution of 11-4 (1.8 g, 5.63 mmol) and THF (30 mL) at 0°C. was added NaH (248 mg, 6.19 mmol). After 30 minutes, TosCl was addedfollowed by the removal of the cooling bath. After 1.0 hour, thereaction was diluted with EtOAc and then washed with H₂ O, sat NaHCO₃,brine, dried (MgSO₄) and concentrated. Flash chromatography (silica,40→60% EtOAc/hexanes) gave 12-1 as an oil.

TLC R_(f) =0.75 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 7.72 (d,J=8.30 Hz, 2H), 7.35 (d, J=7.3 Hz, 2H), 7.25 (m, 3H), 7.09 (m 2H), 4.94(d, J=14.9 Hz, 1H), 4.01 (m, 1H), 3.94 (m,5H), 3.83 (d, J=15.1 Hz, 1H),3.54 (m,1H), 2.46 (s,3H), 2.42 (m,1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.72(M, 2H), 1.43 (m, 2H), 1.32 (s, 3H).

1-benzyl-5(S)-benzyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(12-2)

To a stirred suspension of CuI (2.57 g, 13.5 mmol) and Et₂ O (10 mL) at0° C. was added PhLi (14.2 mL, 25.6 mmol, 1.8M cyclohexane-ether)dropwise over a 1.0 hour period. After an additional hour, 12-1 (1.4 g,2.96 mmol), dissolved in 10 mL Et₂ O, was added. The reaction wasstirred at -15° C. for 96 hours. The reaction was diluted with EtOAc andthen washed with sat NH₄ Cl, sat NaHCO₃, brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 30→60% EtOAc/hexanes) gave12-2 as an oil.

TLC R_(f) =0.29 (silica,50% EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.13→7.36 (m, 8H), 7.02 (d, J=7.6 Hz, 2H), 5.06 (d, J=14.9 Hz, 1H), 4.14(d, J=15.1 Hz, 1H), 3.95 (m, 4H), 3.55 (m, 1H), 3.18 (dd, J=4.2, 17.0Hz,1H), 2.35 (m,2H), 2.04 (m,2H), 1.66 (m,2H), 1.32 (m,5H).

5(S)-benzyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one(12-3)

Into a 3-necked 500 mL flask at -78° C. was condensed 100 mL of ammonia.Next, 12-2 (470 mg, 1.24 mmol), dissolved in 20 mL of THF, was added.Lithium (19 mg, 2.48 mmol) was washed with MeOH, then THF and then addedto the ammonia. After 20 minutes, the reaction was quenched with NH₄ Cl;200 mL of THF was added, the cooling bath was removed and the solutionpurged with argon for 30 minutes to remove the ammonia. The solution wasdried (MgSO₄) and concentrated. Flash chromatography (silica, EtOAc)gave 12-3 as an oil.

TLC R_(f) =0.22 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 7.18→7.35(m, 5H), 5.43 (br s, 1H), 3.95 (s, 4H), 3.92 (m 1H), 2.88 (dd, J=5.3,18.6 Hz, 1H), 2.41 (m, 2H), 2.03 (m,1H), 1.71 (m,2H), 1.43 (m,2H), 1.33(s,3H).

{5(S)-benzyl-3(S)-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-2-oxo-pyrrolidin-1-yl}-aceticacid ethyl ester (12-4)

To a stirred solution of 12-3 (210 mg, 0.7257 mmol) and THF (5 mL) at-78° C. was added NaN(TMS)₂ (0.943 mL, 0.943 mmol, 1.0M in THF). After30 min, ethyl bromoacetate (0.104 mL, 0.9434 mmol) was added and thereaction was warmed to 0° C. After 1.0 hour, the reaction mixture wasdiluted with EtOAc and then washed with sat NaHCO₃, brine, dried(MgSO₄), and concentrated to give 12-4 as a yellow oil.

TLC R_(f) =0.64 (silica, EtOAc); ¹ H NMR (300 MHz, CDCl₃) δ 7.15→7.33(m, 5H), 4.40 (d, J=17.8 Hz, 1H), 4.15 (m, 2H), 3.93(m, 5H), 3.77 (d,J=17.8, 1H), 3.07 (dd, J=5.0, 18.6 Hz, 1H), 2.56 (m, 1H), 2.39 (m, 1H),2.20 (m, 1H), 2.05 (m,1H), 1.69 (m, 2H), 1.23→1.46 (m,8H).

[5(S)-benzyl-2-oxo-3(S)-(3-oxo-butyl)-pyrrolidin-1-yl]-acetic acid ethylester (12-5)

A solution of 12-4 (260 mg, 0.6925 mmol), p-TSA (10 mg) and acetone (20mL) was heated at reflux for 1 hr. NaHCO₃ was added to the cooledreaction mixture and then the mixture was concentrated. The residue wasdiluted with CHCl₃ and then washed with brine, dried (MgSO₄), andconcentrated to afford 12-5 as an oil.

TLC R_(f) =0.66 (silica, 75%EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ7.22→7.36 (m, 3H), 7.15 (d, J=6.5 Hz, 2H), 4.37 (d, J=17.6 Hz, 1H), 4.18(m, 2H), 3.97 (m, 1H), 3.77 (d, J=17.8 Hz, 1H), 3.06 (dd, J=5, 18 Hz,1H), 2.60 (m, 3H), 2.42 (m, 1H), 2.17 (m, 1H), 2.14 (s, 3H), 1.96(m,1H), 1.74 (m, 1H) 1.27 (m, 4H).

[5(S)-benzyl-3(S)-(2-[1,8]naphthyridin-2-yl-ethyl)-2-oxo-pyrrolidin-1-yl]-aceticacid ethyl ester (12-6)

A mixture of 12-5 (230 mg, 0.6940 mmol), 1-4, (2-amino-3-formylpyridine,110 mg, 0.9022 mmol) and proline (80 mg, 0.6940 mmol) in absoluteethanol (10 mL) was heated at reflux for 18 h. Following evaporativeremoval of the solvent, the residue was chromatographed (silica gel,70:28:2 chloroform/ethyl acetate/MeOH) to give 12-6 as a yellow oil.

TLC Rf=0.38 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 9.08 (m, 1H), 8.16 (dd, J=2 Hz, 10 Hz 1H), 8.09 (d,J=8.3 Hz,1H), 7.44 (m, 2H), 7.28 (m, 2H), 7.16 (d, J=8 Hz, 2H), 4.37 (d, J=17.6Hz, 1H), 4.16 (m, 2H), 3.96 (m, 1H), 3.80 (d, J=17.6 Hz, 1H), 3.15 (m,2H), 3.06 (dd, J=5.3, 18.5, 1H), 2.26→2.63 (m, 4H), 1.97 (m, 1H), 1.47(m, 1H), 1.25 (t, J=7.1 Hz, 3H).

{5(S)-benzyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-aceticacid ethyl ester (12-7)

A mixture of 12-6 (220 mg, 0.5270 mmol) and 10% Pd/carbon (100 mg) inEtOH (4 mL) was stirred under a balloon of hydrogen for 2 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH togive 12-7 as a colorless oil.

TLC Rf=0.25 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 7.26 (m, 3H), 7.16 (d, J=8.1 Hz, 2H), 7.04 (d, J=7.3 Hz, 1H),6.36 (d, J=7.3 Hz, 1H), 4.74 (br s, 1H), 4.39 (d, J=17.8 Hz, 1H), 4.15(m, 2H), 3.90 (m, 1H), 3.77 (d, J=17.5 Hz, 1H), 3.38 (m, 2H), 3.06 (dd,J=2.4, 18.8 Hz, 1H), 2.65 (m, 5H), 2.43 (m, 1H), 2.22 (m, 3H), 1.89 (m,1H) 1.36 (m,1H), 1.26 (t, J=7.1 Hz, 3H).

{5(s)-benzyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-aceticacid hydrochloride (12-8)

A mixture of 12-7 (150 mg, 0.3559 mmol) and 6N HCl (10 mL) was heated at60° C. for 1 h. Evaporative removal of the solvent gave 12-8 as a yellowsolid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.57 (d, J=7.3 Hz, 1H), 7.24 (m, 5H), 6.60(d, J=7.3 Hz, 1H), 4.24 (d, J17.8, Hz, 1H), 4.03 (m, 2H), 3.49 (t, J=5.6Hz, 2H), 3.15 (dd, J=4.4, 17.6 Hz, 1H), 2.71 (m, SH), 2.46 (m, 1H), 2.21(m, 1H), 1.97 (m,3H), 1.64 (m, 1H), 1.45 (m,1H)

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanineethyl ester (12-9)

A mixture of 12-8 (150 mg, 0.3559 mmol), 2-10 (60 mg, 0.2135 mmol), EDC(132 mg, 0.7118 mmol), HOBT (48 mg, 0.3559mmol) and NMM (0.4 mL, 2.85mmol) in DMF (4 mL) was stirred for 20 h. The mixture was diluted withethyl acetate, washed with sat. NaHCO₃, brine, and dried over MgSO₄.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH togive 12-9 as a colorless foam.

TLC Rf=0.15 (70:25:5 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CD₃ OD) δ 8.55 (s, 1H), 8.44 (m, 1H), 7.82 (m, 1H), 7.6-7.1 (m, 7H),6.33 (d, J=7.5 Hz, 1H), 5.40 (t, J=8 Hz, 1H), 4.2-3.8 (m, 6H), 3.38 (m,1H), 3.17 (m, 2H), 2.90 (m, 2H), 2.67 (m, 2H), 2.54 (m, 2H), 2.12 (m,2H),1.84 (m, 2H), 1.43 (m, 2H) 1.18 (m, 3H).

2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine(12-13)

To a solution of 12-9 (70 mg, 0.1229 mmol) in EtOH (1 mL) was added 1NNaOH (0.150 ml, 0.150 mmol). After stirring for 1.5 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 25:10:1:1 to15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH to give 12-10 as a colorlessfoam.

TLC Rf=0.21 (10: 10:1:1 ethyl acetate/EtOH/water/NH₄ OH). ¹ H NMR (300MHz, CD₃ OD) δ 8.62 (s, 1H), 8.36 (m, 1H), 7.92 (m, 1H), 7.45-7.2 (m,7H), 6.49 (d, J=7.1 Hz, 1H), 5.27 (m, 1H), 4.31 (d, J=17.3 Hz, 1H), 3.93(m, 1H), 3.72 (d, J=17.5 Hz, 1H), 3.30 (m, 3H), 2.92-2.52 (m, 8H), 2.36(m, 2H), 1.90 (m, 3H), 1.57 (m, 1H). ##STR46##1-benzyl-5(S)-hydroxymethyl-pyrrolidin-2-one (13-1)

A mixture of 11-2 (5.0 g, 24.6 mmol), 10% Pd/C (2.5 g), and ethanol (80mL) was stirred at ambient temperature under a hydrogen atmosphere (1atm) for 5 hr. The catalyst was removed by filtration through a celitepad and the filtrate concentrated to give 13-1 as a colorless oil.

TLC RF=0.55 (silica, 70:20:10 CHCl₃ /EtOAc/CH₃ OH); ¹ H NMR (300 MHz,CDCl₃) δ 7.29 (m, 5H), 4.83 (d, 2H, J=15H), 4.25 (d, 1H, J=15 Hz), 3.77(m, 1H), 3.51 (m, 2H), 2.54 (m, 1H), 2.40 (m, 1H), 1.92 (m, 2H).

1-benzyl-5(S)-iodomethyl-pyrrolidin-2-one (13-2)

To a solution of 13-1 (18.5 g, 90.1 mmol), triphenylphosphine (40.1 g,153 mmol), and imidazole (11.03 g, 162 mmol) in 225 mnL of acetonitrileand 150 mL of ether at 0° C. was added iodine (34.3 g, 135 mmol) in 5portions over 5 minutes. After 10 minutes, the reaction was heated to50° C., and a stream of argon passed over the reaction to purge theevaporating ether. After an additional 30 minutes, the mixture wasdiluted with ether, the organic layer washed with NaHCO₃ (sat.) andbrine, dried over K₂ CO₃, and the solvent evaporated. Flashchromatography of the residue (silica, 7-15% EtOAc/CHCl₃) gave 13-2 as ayellow oil.

TLC R_(f) =0.53 (silica, 30% EtOAc/CHCl₃); ¹ H NMR (300 MHz, CDCl₃) δ7.31 (m,5H), 5.05 (d, 1H, J=15 Hz), 3.92 (d, 1H, J=15 Hz), 3.41 (m, 1H),3.26 (m, 2H), 2.62 (m, 1H), 2.43 (m, 1H), 2.16 (m, 1H), 1.81 (m, 1H).

1-benzyl-5(R)-methyl-pyrrolidin-2-one (13-3)

To a solution of 13-2 (22.1 g, 70 mmol) in 200 mL ofhexamethylphosphorous triamide at 0° C. was added NaBH₄ (5.25 g, 140mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction wasallowed to warm to ambient temperature and stirred for 2 h. The mixturewas diluted with 1:1 ether/hexanes, quenched by the careful addition of300 mL 10% KHSO₄ (aq), separated, the organics dried over K₂ CO₃, andthe solvent evaporated to give 13-2 as a yellow oil

TLC R_(f) =0.45 (silica, 30% EtOAc/CHCl₃); ¹ H NMR (300 MHz, CDCl₃) δ7.32 (m, 5H), 4.95 (d, 1H, J=15 Hz), 4.00 (d, 1H, J=15 Hz), 3.52 (m,1H), 2.46 (m, 2H), 2.15 (m, 1H), 1.60 (m, 1H), 1.16 (d, 3H, J=6.0 Hz)).

3(R)-azido-1-benzyl-5(R)-methyl-pyrrolidin-2-one (13-4)

To a solution of 13-3 (2.2 g, 11.6 mmol) in THF (45 mL) at -78° C. wasadded a solution of LDA (6.39 mL, 12.8 mmol; 2M/THF, ethylbenzene). Themixture was warmed to -15° C. for 20 minutes, then recooled to -78° C.,and 2,4,6-triisopropylbenzenesulfonyl azide (4.31 g, 13.9 mmol, preparedas described in Harmon, et al, J. Org. Chem. 1973, 38, 11-16. ) wasadded rapidly as a solution in 40 mL THF at -78° C. After 10 minutes,glacial acetic acid (2.67 mL, 47 mmol) was added, and the resultantviscous liquid mixture allowed to warm to ambient temperature and stirfor 1 hour. The solvent was then evaporated, the residue dissolved inCHCl₃, washed with NaHCO₃ (sat.), and dried over magnesium sulfate.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 25% ethyl acetate/hexanes) to give 13-4 asa colorless oil.

TLC Rf=0.38 (25% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ 7.32(m, 5H), 5.00 (d, 1H, J=15 Hz), 4.27 (t, 1H, J=7.5 Hz), 3.98 (d, 1H,J=15 Hz), 3.54 (m, 1H), 1.97 (m, 2H), 1.16 (d, 3H, J=6.0 Hz).

3(S)-azido-1-benzyl-5(R)-methyl-pyrrolidin-2-one

To a solution of 13-4 (2.17 g, 9.42 mmol) in EtOH (50 mL) was added asolution of NaOEt (3.52 mL, 9.42 mmol; 2.68 M/EtOH). The mixture wasstirred for 90 minutes, then quenched by the addition of glacial aceticacid (3 mL). The solvent was then evaporated, the residue slurried inEtOAc, washed with NaHCO₃ (sat.), and dried over K₂ CO₃. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 17% ethyl acetate/hexanes) to give 13-5 as a colorless oiland 13-4 as a colorless oil.

TLC Rf=0.44 (25% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ 7.32(m, 5H), 4.97 (d,1H, J=15 Hz), 4.17 (t, 1H, J=7.5 Hz), 4.05 (d, 1H, J=15Hz), 3.44 (m, 1H), 2.48 (m, 2H), 1.50 (m, 1H), 1.22 (d, 3H, J=6.6 Hz).

(1-benzyl-5(R)-methyl-2-oxo-pyrrolidin-3(S)-yl)-carbamic acid tert-butylester (13-6)

A mixture of 13-5 (2.38 g, 10.3 mmol), 10% Pd/C (1.0 g), TFA (10 mL),THF (80 mL) and methanol (100 mL) was stirred at ambient temperatureunder a hydrogen atmosphere (1 atm) for 3 hr. The catalyst was removedby filtration through a celite pad and the filtrate concentrated to givethe intermediate amine salt as a colorless oil. To a solution of thecrude amine salt in THF (50 mL) at 0° C. was added NEt₃ (2.88 mL, 20.7mmol) and di-tert-butyl dicarbonate (2.59 g, 11.9 mmol). The mixture wasallowed to warm to ambient temperature and stir for 4 hours. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 40% ethyl acetate/hexanes) to give 13-6 as a colorless oil.

TLC RF=0.44 (silica, 40% ethyl acetate/hexanes); ¹ H NMR (300 MHz,CHCl₃) δ 7.31 (m, 5H), 5.17 (br s, 1H), 4.94 (d, 1H, J=15 Hz), 4.20 (m,1H), 4.07 (d, 1H, J=15 Hz), 3.44 (m, 1H), 2.77 (m, 1H), 1.45 (s, 9H),1.20 (d, 3H, J=7 Hz).

(5(R)-methyl-2-oxo-pyrrolidin-3(S)-yl)-carbamic acid tert-butyl ester(13-7)

To a blue solution of lithium metal (0.237 g, 34.2 mmol) in NH₃ (1) (200mL) at -78° C. was added a solution of 13-6 (2.60 g,8.54 mmol) in THF(15 mL). The mixture was stirred for 15 minutes, then quenched by theaddition of ammonium chloride until the blue color dispersed. Anadditional 30 mL of THF was added, and the mixture warmed to 35° C. toevaporate the ammonia. MgSO₄ was added,the mixture was filtered througha celite pad. Following evaporative removal of the solvent, the residuewas chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH)to give 13-7 as a colorless oil

TLC Rf=0.45 (70:20:10 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CHCl₃) δ 6.97 (br s, 1H), 5.24 (d,1H, J=7.6 Hz), 4.32 (br s, 1H), 3.66(m, 1H), 2.79 (m, 1H), 1.45 (s, 9H), 1.25 (d, 3H, J=6.0 Hz).

(3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)-aceticacid ethyl ester (13-8)

To a solution of 13-7 (1.83 g, 8.4 mmol) in THF (22 mL) at -78° C. wasadded sodium bis(trimethylsilyl)amide (9.4 mL, 9.4 mmol; 1M/THF)dropwise. After an additional 20 min, ethyl bromoacetate (1.13 mL, 10.3mmol) was added dropwise. After an additional 20 minutes, the mixturewas allowed to warm to 0° C., and 20 mL sat. aqueous NH₄ Cl was added.The layers were separated, the aqueous layer washed with EtOAc, and thecombined organic extracts were dried over K₂ CO₃. Following evaporativeremoval of the solvent, the residue was chromatographed (silica gel, 40%ethyl acetate/hexanes) to give 13-8 as a colorless oil.

TLC Rf=0.39 (40% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ 5.20(br s, 1H), 4.38 (d,1H, J=18 Hz), 4.21 (m, 3H), 3.77 (m, 2H), 2.83 (m,1H), 1.44 (s, 9H), 1.23 (m, 6H).

(3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)-aceticacid (13-9)

To a solution 13-8 (527 mg, 1.75 mmol) in EtOH was added 1N NaOH (1.93mL, 1.925 mmol). After stirring for 1 h, the solvents were evaporated,the mixture was diluted with EtOAc, acidified with 10% KHSO₄, washedwith brine, dried over MgSO₄, and evaporated to give 13-9 as a whitesolid.

TLC R_(f) =0.48 (silica, 9.5/0.5/0.5 CH₂ Cl₂ /MeOH/AcOH); ¹ H NMR (300MHz, CD₃ OD) δ 4.21 (m, 2H), 3.85 (d, 1H, J=18 Hz), 3.74 (m, 1H), 2.58(m, 1H), 1.52 (m, 1H), 1.44 (s, 9H), 1.25 (d, J=6.3 Hz, 3H).

(3(S)-tert-butoxycarbonylamino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)-acetyl-3(S)-ethynyl-β-alanineethyl ester (13-10)

A mixture of 13-9 (440 mg, 1.62 mmol), 2-9 (290 mg, 1.62 mmol), EDC (373mg, 1.94 mmol), HOBT (262 mg, 1.94 mmol) and NMM (1.20 mL, 11.34 mmol)in CH₃ CN (5 mL) was stirred for 20 h. The mixture was diluted withEtOAc, washed with sat. NaHCO₃, brine, and dried over MgSO₄. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, EtOAc) to give 13-10 as a colorless foam.

TLC Rf=0.20 (silica, EtOAc). ¹ H NMR (300 MHz, CDCl₃) δ 7.31 (bd, 1H),5.33 (bd, 1H), 5.21 (m, 1H), 4.16 (m, SH), 3.64 (m, 2H), 2.72 (m, 2H),2.45 (d, J=2.2 Hz, 1H), 1.52 (m, 1H), 1.46 (s, 9H), 1.27 (m, 6H).

(3(S)-amino-5(R)-methyl-2-oxo-pyrrolidin-1-yl)-acetyl-3(S)-ethynyl-β-alanineethyl ester hydrochloride (13-11)

To a solution of 13-10 (550 mg, 1.39 mmol) in EtOAc at 0° C. was bubbledHCl gas for 5 minutes. The reaction was stirred an additional 5 minutes,followed by removal of the cooling bath and then purged with Argon for20 minutes. Evaporative removal of the solvent gave 13-11 as a whitesolid.

¹ H NMR (300 MHz, CD₃ OD) δ 5.02 (m, 1H), 4.12 (m, 4H), 3.83 (m, 2H),2.77 (m, 2H), 1.59 (m,1H), 1.25 (m, 6H).

5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanineethyl ester (13-12)

To a solution of 13-11 (450 mg, 1.39 mmol) and5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde (225 mg, 1.39 mmol)in dichloroethane at 0° C. was added Na(OAc)₃ BH. After 1.5 h thereaction was quenched with sat. NaHCO₃, diluted with EtOAc, washed withsat. NaHCO₃, brine and dried over MgSO₄. Following evaporative removalof the solvent, the residue was chromatographed (silica gel, 70:20:10chloroform/ethyl acetate/MeOH to give 13-12 as a colorless foam.

TLC Rf=0.17 (70:15:15 chloroform/ethyl acetate/MeOH). ¹ H NMR (300 MHz,CDCl₃) δ 7.09 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.48 (d, J=7.3Hz, 1H), 5.05 (m, 1H), 4.83 (bs, 1H), 4.17 (q, J=6.4, 1H), 3.92 (m, 2H),3.74 (m, 2H), 3.58 (m, 4H), 3.40 (m, 2H), 2.70 (m, 4H), 2.54 (m, 1H),2.26 (s, 1H), 1.90 (m, 2H), 1.55 (m, 2H), 1.25 (m, 6H).

5(R)-methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine(13-13)

To a solution of 13-12 (108 mg, 0.24 mmol) in EtOH (2 mL) was added 1NNaOH (0.270 ml, 0.264 mmol). After stirring for 1 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 25:10:1:1 to15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH) to give 13-13 as a colorlessfoam.

TLC Rf=0.23 (12:10:1:1 ethyl acetate/EtOH/water/NH₄ OH). ¹ H NMR (300MHz, D₂ O) δ 7.53 (d, 1H, J=7.3 Hz), 6.69 (d, 1H, J=7.3 Hz), 4.41 (m,2H), 3.71 (m, 2H), 3.45 (t, J=5.8 Hz, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.6(m, 4H), 1.92 (m, 3H), 1.50 (m, 1H), 1.19 (m, 3H). ##STR47##2-Dimethoxymethyl-[1,8]naphthyridine (14-1)

A mixture containing 1-4 (30 g, 0.245 mol), pyruvaldehyde dimethylacetal(87 g, 0.737 mol), and L-proline (7.0 g, 0.062 mol) in MeOH (300 mL) wasrefluxed under argon for 16 h. The cooled solution was filtered,evaporated and the residue dissolved in CH₂ Cl₂ (500 mL) and washed withwater and brine then dried and concentrated to a volumn of ca. 100 mL.Hexane (300 mL) was added and the mixture was kept at 0° C. for 3 h,then filtered affording 14-1 as an off-white crystalline solid.

¹ H NMR (300 MHz, CDCl₃) δ 9.14 (d, J=2.2 Hz, 1H); 8.26 (d, J=8.7 Hz,1H); 8.21 (dd, J=8.7, 2.2 Hz, 1H); 7.8 (d, J=8.3 Hz, 1H); 7.5 (m, 1H);5.48 (s, 1H); 3.53 (s, 6H).

2-Dimethoxymethyl-5,6,7,8-tetrahydro-[1,8]naphthyridine (14-2)

A solution 14-1 (10 g, 0.049 mol) in MeOH, (100 ml) was treated with 10%Pd on C (1.5 g) and the resulting mixture stirred under a H₂ filledballoon for 12.5 h. The catalyst was removed by filtration throughcelite and the solution concentrated to afford 14-2 as a yellowcrystalline solid.

¹ H NMR (300 MHz, CDCl₃) δ 7.18 (d, J=7.12 Hz, 1H); 6.71 (d, J=7.12 Hz,1H); 5.18 (s, 1H); 4.96 (br, s, 1H); 3.43 (s, 6H); 3.4 (m, 2H); 2.65 (m,2H); 1.91 (m, 2H).

5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (14-3)

14-2 (10 g, 0.048 mol) was trifluoroacetic acid (50 mL) and theresulting solution stirred under argon for 12.5 h. The TFA was removedat reduced pressure and the residue partitioned between sat. NaHCO₃ andCH₂ Cl₂. The organic layer was dried, concentrated and passed through a3 in. pad of silica gel (10% acetone/CH₂ Cl₂) and concentrated to afford14-3 as a yellow crystalline solid.

¹ H NMR (300 MHz, CDCl₃) δ 9.80 (s, 1H); 7.31 (d, J=7.32 Hz, 1H); 7.16(d, J=7.32 Hz, 1H); 5.31 (br, s, 1H); 3.48 (m, 2H); 2.81 (m, 2H); 1.94(m, 2H). ##STR48## 1-Bromo-3-(2,2-diethoxy-ethoxy)-benzene (15-2)

To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0° C. wasadded a solution of 3-bromophenol 15-1 in DMF (40 mL) over 40 min. Afterthe addition was complete, the solution was stirred for an additional 30min. The solution was then treated with neat bromoacetaldehyde diethylacetal (17.36 g, 115.6 mmol). The solution was heated at 100° C. for 8h, cooled to room temperature, and extracted with Et₂ O (3×200 mL). Thecombined organic extracts were washed with 10% aq NaOH (100 mL) andbrine (100 mL), dried over MgSO₄, filtered and concentrated to give 15-2as a yellow oil.

TLC Rf=0.4 (10% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ7.19-7.05 (m, 3H), 6.85 (d, 1H), 4.81 (t, 1H, J=6.8 Hz), 3.99 (d, 2H,J=6.8 Hz), 3.71 (m, 4H), 1.22 (t, 6H, J=7.1 Hz) ppm.

6-Bromo-benzofuran (15-3)

To a solution of the acetal 15-2 in toluene (200 mL) was addedpolyphosphoric acid (20 g). The biphasic mixture was heated to 100° C.and stirred at this temperature for 4 h. The mixture was cooled to roomtemperature, poured onto ice, and extracted with Et₂ O (2×200 mL). Thecombined organic extracts were washed with saturated aq NaHCO₃ andbrine. The solution was dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (100% hexanes) to givethe product 15-3 as a yellow oil.

TLC Rf=0.3 (100% hexanes). ¹ H NMR (300 MHz, CHCl₃) δ 7.68 (s, 1H), 7.60(d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz),6.75 (dd, 1H, J=7.1, 0.9 Hz) ppm.

3-Benzofuran-6-yl-acrylic acid ethyl ester (15-4)

A mixture of the 6-bromobenzofuran 15-3 (1.74 g, 8.79 mmol), ethylacrylate (1.09 g, 10.98 mmol), Pd(OAc)₂ (0.099 g, 0.44 mmol),tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g,43.9 mmol) in DMF (10 mL) was heated to 100° C. in a sealed tube for 4h. The mixture was cooled to room temperature, diluted with water, andextracted with Et₂ O (2×40 mL). The combined organic extracts werewashed with brine (30 mL), dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (10% ethylacetate/hexanes) to give the ester 15-4 as an off-white solid.

TLC Rf=0.3 (10% ethyl acetate/hexanes). ¹ H NMR (300 MHz, CHCl₃) δ 7.78(d, 1H, J=15.9 Hz), 7.68 (d, 1H, J=2.4 Hz), 7.66 (s, 1H), 7.59 (d, 1H,J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5 Hz), 6.78 (m, 1H), 6.47 (d, 1H,J=15.9 Hz), 4.27 (q, 2H, J=7.2 Hz), 1.34 (t, 3H, J=7.2 Hz) ppm.

3-(S)-Benzofuran-6-yl-3-[benzyl-(1(R)-phenyl-ethyl)-amino]-propionicacid ethyl ester (15-5)

A solution of benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF(25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5 M soln inhexanes). The resulting solution was stirred at 0° C. for 30 min andthen cooled to -78° C. A solution of acrylate 15-4 (0.681 g, 3.15 mmol)in THF (5 mL) was added. After stirring for 15 min at -78° C., satd aqNH₄ Cl soln (5 nmL) was added and the cold bath removed. The mixture waswarmed to room temperature, and extracted with Et₂ O (2×40 mL). Thecombined organic extracts were washed with brine (30 mL), dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (10% ethyl acetate/hexanes) to give the β-aminoester 15-5as a yellow oil.

TLC Rf=0.8 (10% ethanol/dichloromethane). ¹ H NMR (300 MHz, CHCl₃) δ7.58 (m, 3H), 7.41 (m, 2H), 7.22 (m, 9H), 7.59 (s, 1H), 4.58 (m, 1H),4.05 (m, 1H), 3.91 (q, 2H, J=7.1 Hz), 3.72 (m, 2H), 2.62 (m, 2H), 1.21(d, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.1 Hz) ppm.

3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester(15-6)

A mixture of the dibenzylamine 15-5 (1.19 g, 2.78 mmol) in EtOH/H₂O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated withPd(OH)2 (1.19 g). The mixture was placed under 1 atm of H₂. Afterstirring for 18 h, the mixture was diluted with EtOAc, and filteredthrough celite. The filtrate was concentrated and the residue purifiedby flash chromatography (10% ethyl acetate/dichloromethane) to give theester 15-6 as a white solid.

TLC Rf=0.25 (10% ethanol/dichloromethane). ¹ H NMR (300 MHz, CD₃ OD) asthe trifluoroacetate salt: δ 7.25 (d, 1H, J=8.1 Hz), 6.88 (m, 1H), 7.66(s, 1H), 6.82 (s, 1H), 4.58 (m, 3H), 4.12 (m, 2H), 3.30 (m, 1H), 3.19(m, 2H), 2.98 (m, 2H), 1.11 (t, 3H, J=7.2 Hz) ppm.

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid ethyl ester (15-7)

A solution of the amine 15-6 (0.100 g, 0.425 mmol), acid 3-11 (0.155 g,0.511 mmol), EDC (0.098 g, 0.511 mmol), NMM (0.103 g, 1.02 mmol), andHOAT (0.069 g, 0.511 mmol) in DMF (6 mL) was stirred at room temperaturefor 48 h. The solution was diluted with satd aq NaHCO₃ (3 mL) andextracted with EtOAc (2×10 mL). The combined organic extracts werewashed with brine (10 mL), dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (8%ethanol/dichloromethane) to give the ester 15-7 as an yellow oil.

TLC Rf=0.3 (10% ethanol/dichloromethane). ¹ H NMR (300 MHz, CHCl₃) δ7.12 (m, 2H), 6.78 (m, 1H), 6.65 (s, 1H), 6.39 (m, 1H), 5.36 (m,1H),4.99 (br s, 1H), 4.55 (t, J=7.2 Hz, 2H), 4.11 (m, 2H), 3.91 (m, 2H),3.39 (m, 2H), 3.19 (m, 2H), 2.79 (m, 2H), 2.70 (m, 2H), 2.51 (m, 1H),2.28 (m, 2H), 1.85 (m, 3H), 1.18 (m, 3H) ppm.

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionicacid (15-8)

A solution of the ester 15-7 (0.038 g, 0.073 mmol) in EtOH/H₂ O (4.5mL/0.5 mL) was treated with LiOH (0.009 g, 0.365 mmol) and thehomogeneous solution stirred at room temperature for 4 h. The solutionwas concentrated to a solid residue which was dissolved in H₂ O andpurified by preparative HPLC (gradient conditions: 95:05 to 50:50 H₂O/MeCN with 0.1% TFA) to give the acid 15-8 as a white solid (as thebis-trifluoroacetate salt).

MS (LR, FAB) M+1 calcd 493, found 493.39. ¹ H NMR (300 MHz, CHCl₃) δ7.91 (m, 1H), 7.35 (m, 1H), 7.09 (m, 1H), 6.76 (m, 1H), 6.68 (s, 1H),6.43 (m, 2H), 5.28 (m, 1H), 4.53 (m, 2H), 4.41 (m, 1H), 3.38 (m, 7H),3.14 (m, 3H), 2.81 (m, 5H), 2.60 (m, 1H), 2.28 (m, 1H), 2.05 (m, 3H)ppm. ##STR49## 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone (16-2).##STR50## DPPA (35.6 ml, 165 mmol) was added to a stirred solution of2-hydroxy-6-methylpyridine-3-carboxylic acid (16-1; Aldrich; 22.97 g,165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml)and the resulting solution was-heated to reflux. After 16 h moretriethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 165 mmol)were added and the solution was refluxed for a further 24 h. Thereaction was concentrated in vacuo to remove most of the volatiles. Theresidue was partitioned between methylene chloride (500 ml) and brine(500 ml), acidified to pH 1 with 1 M HCl (165 ml). The aqueous layer wasextracted methylene chloride (two times) and the combined organic layerswere washed with sodium hydrogen carbonate solution and brine, dried(Na₂ SO₄) and evaporated in vacuo to a brown solid. This wasrecrystallized from methanol, to give the title compound 16-2 as a tansolid: ¹ H NMR (300 MHz, CDCl₃) δ 2.29 (s, 3H, CH₃), 5.20 (s, 2H,PhCH₂), 6.06 (d, J=7.6 Hz, pyridinone-5-H), 7.32-7.43 (m, 5H, Ph), 7.67(br s, 1H, CbzNH), 8.03 (br d, pyridinone-4-H).

2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl]acetic acidt-butyl ester (16-3). ##STR51## Sodium hydride (5.3 g, 0.22 mol) wasadded to a stirred slurry of3-benzyloxycarbonylamino-6-methyl-2-pyridinone (16-2; 53.2 g, 0.20 mol)in THF at 0° C. t-Butylbromoacetate (45 ml, 0.27 mol) was added to theresulting solution and a precipitate rapidly forms. The reaction waswarmed to rt over 1 h and after 2 h the solvent was evaporated in vacuoand the residue was partitioned between 1:1 water/brine (200 ml) and 6:1THF/methylene chloride (700 ml). The organic layer was dried (Na₂ SO₄)and evaporated in vacuo to a solid which was triturated with hexane togive the title compound 16-3 as a crystalline solid:

¹ H NMR (400 Mz, CDCl₃) δ 1.47 (s, 9H), 2.25 (s, 3H), 4.75 (s, 2 H),5.19 (s, 2H), 6.09 (d, J=7.8 Hz), 7.30-7.40 (m, 5H), 7.75 (br s, 1H),7.94 (br d, 1H).

2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl]acetic acid(16-4). ##STR52## HCl gas was bubbled through a stirred suspension of2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl]acetic acidt-butyl ester (16-3; 12.3 g, 33 mmol) in ethyl acetate (250 ml) at -15°C. for 20 min. The resulting solution was allowed to warm to roomtemperature and was then stirred there for 3 h. After purging withargon, the bulk of the solvent was rotavapped off and ether added to theresidue. The solid which precipitated was filtered off and washed withether. The title compound 16-4 was thus obtained as a white fluffypowder: ¹ H NMR (CD₃ OD) δ 2.32 (s, 3 H), 4.86 (s, 2 H), 5.18 (s, 2 H),6.24 (d, J=7.9 Hz, 1 H), 7.31-7.41 (m, 6 H), 7.94 (br s, 1 H).

3-(2-{6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid ethyl ester (16-5). ##STR53## To a solution of the acid 2-4 (150mg, 0.47 mmol) and the amine 1-9 (Rico et al; J. Org. Chem., 1993, 58,7948; 139 mg, 0.52 mmol) in DMF (3 mL) was added HOBT (77 mg, 0.57 mmol)then Et₃ N (200 μL, 1.42 mmol). After 15 minutes, EDC (136 mg, 0.71mmol) was added and the mixture was stirred for 16 hours. The solutionwas poured into EtOAc, washed with saturated NaHCO₃ then brine, dried(MgSO₄), and evaporated to give the title compound 16-5 as a white solidwhich was used as such in the next step. ¹ H NMR (CDCl₃) δ 1.14 (3H, t),2.40 (3H, s), 2.8-2.9 (2H, m), 4.05 (2H, q), 4.78 (2H, m), 5.22 (2H, s),5.4 (1H, q), 6.17 (1H, d), 7.22 (1H, m), 7.3-7.45 (4H, m), 7.59 (1H, m),7.7-7.8 (2H, m), 8.0 (1H, m), 8.52 (2H, m).

3-(2-{6-methyl-2-oxo-3-amino-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid ethyl ester (16-6). ##STR54## To a degassed solution of thepyridone 16-5 (243 mg; 0.49 mmol) in EtOH (20 mL) was added 10% Pd oncarbon (25 mg) and this was then stirred under an atmosphere of hydrogengas (balloon) for 3 hours. The mixture was filtered through a pad ofcelite and the solvent removed to give the title compound (16-6) as aviscous oil which was used as such in the next step.

3-(2-{6-methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid ethyl ester (16-7). ##STR55## To a solution of the amine 16-6 (155mg, 0.433 mmol), the aldehyde 14-3 (70 mg, 0.433 mmol) in CH₂ ClCH₂ Clwas added crushed 4A seives, AcOH (20 μL) and then NaB(OAc)₃ H (184 mg,0.866 mmol). After stirring for 48 hours, the mixture was filteredthrough celite, poured into EtOAc and washed with saturated NaHCO₃ thenbrine. The dried (MgSO₄) solution was concentrated in vacuo to give afoam type solid. Column chromatography (5%MeOH in CHCl₃) afforded thetitle compound 16-7 as a foam type solid.

Analysis calculated for C₂₇ H₃₂ N₆ O₄.0.25CHCl₃ C, 61.24; H, 6.08; N,15.73 found C, 61.33; H, 6.09; N, 15.85. FAB mass spectrum. m/z=505.34(M+H)

3-(2-{6-methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionicacid bis trifluoroacetate (16-8). ##STR56## The ester 16-7 (120 mg,0.238 mmol) was dissloved in H₂ O (1 mL) and THF (1 mL) and then 1N LiOH(1 mL, 1 mmol) was added. After 2 hours, the mixture was purified byreverse phase HPLC (Waters PrepPak C18 column eluting with H₂O/acetonitrile gradient) to give, after lyophilization, the titlecompound 16-8 as a powder.

Analysis calculated for C₂₅ H₂₈ N₆ O₄.2.5TFA.0.55H₂ O C, 46.70; H, 4.13;N, 10.89 found C, 46.70; H, 4.14; N, 11.04. FAB mass spectrum. m/z=477.2(M+H) ##STR57## β-N,N-Dimethylaminoethenylcyclopropyl ketone (17-2).##STR58##

A mixture of cyclopropyl methyl ketone (5.88 ml, 59 mmol) andN,N-dimethylformaldehyde dimethyl acetal (7.83 ml, 59 mmol) was heatedin the presence of a catalytic quantity of p-toluenesuffonic acid for 48hours. The resulting crude sample of the title compound (17-2, a paleyellow oil) was used in subsequent reactions without furtherpurification: ¹ H NMR (CDCl₃) δ 0.74 (m, 2 H), 1.00 (m, 2 H), 1.75 (m, 1H), 3.48 (s, 3 H), 3.50 (s, 3 H), 5.20 (d, 1 H), 7.55 (d, 1 H).

6-Cyclopropyl-3-nitro-2-(1H)-pyridinone (17-3). ##STR59##

A mixture of crude β-N,N-dimethylaminoethenylcyclopropyl ketone (17-2;12 g, <86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidiniumacetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100ml) and piperidine (72 ml)] was stirred at room temperature overnight.Following dilution with water (20 ml), the yellow precipitate wasisolated via filtration and drying in vacuo to yield the title compound17-3: ¹ H NMR (CDCl₃) δ 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H),6.02 (br d, J=8.0 Hz, 1 H), 8.41 (d, J=8.0 Hz, 1 H).

3-Nitro-6-cyclopropyl-1-(t-butyl-carboxymethylene)-2-pyridinone (17-4)##STR60##

Solid 6-cyclopropyl-3-nitro-2-(1H)-pyridinone (17-3; 1.4 g, 7.78 mmol)was added in small portions to a suspension of sodium hydride (260 mg,10.8 mmol) in THF (30 ml) at room temperature. After stirring theresulting solution for 20 min, tert-butylbromoacetate (4 ml, 27 mmol)was added. The mixture was stirred for an additional 30 min. then heatedat 55° C. for 15 hrs. After cooling to room temperature the THF wasevaporated in vacuo and ice carefully added to tile residue to destroyany excess sodium hydride. The resulting miture was extracted with 2:1:1ethyl acetate:ether:chloroform and the extracts dried over magnesiumsulfate. Filtration and evaporation of the filtrate gave a yellow oil asa 3:1 mixture of N and O-alkylated products respectively. Flash columnchromatography eluting with 1:1 hexane/ethyl acetate gave the titlecompound 17-4 as a yellow crystalline solid: ¹ H NMR (CDCl₃) δ 0.94 (m,2 H), 1.18 (m, 2 H), 1.49 (s, 9 H), 1.79 (m, 1 H), 5.04 (s, 2 H), 6.10(d, J=8.1 Hz, 1 H), 8.33 (d; J=8.1 Hz, 1 H).

3-Amino-6-cyclopropyl-1-(t-butyl-carboxymethylene)-2-pyridinone (17-5)##STR61##

A mixture of3-nitro-6-cyclopropyl-1-(t-butyl-methylenecarboxy)-2-pyridinone (17-4;760 mg, 2.58 mmol) and platinum oxide (250 mg) in ethanol (30 ml) wasstirred at 0° C. under an atmosphere of hydrogen for 3 hours. Followingremoval of most of the catalyst by filtration through a bed of Celite,the filtrate was concentrated and the residue purified by flash columnchromatography eluting with 2:1 hexane/ethyl acetate. This yielded thetitle product 17-5 as a viscous orange gum: ¹ H NMR (CDCl₃) δ 0.67 (m, 2H), 0.89 (m, 2 H), 1.49 (s, 9 H), 1.63 (m, 1 H), 4.07 (br s, 2 H), 4.99(s, 2 H), 5.91 (dd, J=1.2 and 7.4 Hz, 1 H), 6.47 (d, J=7.4 Hz, 1 H).

{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-aceticacid tert-butyl ester (17-6) ##STR62## Following the procedure describedfor the synthesis of 16-7, the amine 17-5 was coupled with 14-3 to yieldthe title compound 17-6 as an oil. R_(f) (silica gel; 5% MeOH inCHCl₃)=0.39

{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-aceticacid (17-7). ##STR63## Following the procedure described for thepreparation of 16-8, the ester 17-6 was hydrolysed to give the titlecompound 17-7. ¹ H NMR (CD₃ OD) δ 0.66 (m, 2 H), 0.9 (m, 2 H), 1.78 (m,1 H), 1.9 (m, 2H), 2.75 (m, 2H), 3.4 (m, 2H), 4.6 (br s, 2 H), 6.02 (d,1H), 6.19 (d, 1H), 6.58 (m, 1 H), 7.27 (m, 1H).

Ethyl 3-amino-3(S)-(3-fluorophenyl)propionate hydrochloride (17-8)##STR64## The title compound was prepared starting from3-fluorobenzaldehyde (Aldrich) by conversion to ethyl 3-fluorocinnamateand employing the asymmetric addition/hydrogenolysis methodologydescribed by Rico et al; J. Org. Chem., 1993, 58, 7948.

¹ H NMR (CD₃ OD) δ 1.21 (t, 3H), 3.03 (dd, 1H), 3.13 (dd, 1H), 4.15 (q,2H), 4.77 (t, 1H), 7.19 (m, 1H), 7.3 (m, 2H), 7.5 (m, 1H).

3-(2-{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]2H-pyridin-1-yl}-acetylamino)-3(S)-(3-fluorophenyl)propionicacid ethyl ester (17-9) ##STR65## Following the procedure described forthe preparation of 16-5, the acid 17-7 was coupled with the amine 17-8to yield the title compound 17-9.

Analysis calculated for C₃₀ H₃₄ N₅ O₄ F₁.0.25H₂ O C, 65.26; H, 6.30; N,12.69 found C, 65.20; H, 6.04; N, 13.00. FAB mass spectrum. m/z=548.12(M+H)

3-(2-{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]2H-pyridin-1-yl}-acetylamino)-3(S)-(3-fluorophenyl)propionicacid ditrifluoroacetate (17-10) ##STR66## Following the proceduredescribed for the preparation of 16-8, the ester 17-9 was hydrolysed togive the title compound 17-10.

Analysis calculated for C₂₈ H₃₀ N₅ O₄ F₁.2.15TFA.0.5H₂ O C, 55.16; H,4.91; N, 10.62 found C, 55.19; H, 4.91; N, 10.89. FAB mass spectrum.m/z=520.05 (M+H)

3-(2-{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]2H-pyridin-1-yl}-acetylamino)-3(S)-(3-pyridyl)-propionicacid ditrifluoroacetate (17-11). ##STR67## Following the proceduresdescribed for Scheme 16, the acid 17-7 was coupled with the amine 1-9followed by saponification of the ester to afford the title compound17-11.

Analysis calculated for C₂₇ H₃₀ N₆ O₄.2.5TFA.0.6H₂ O C, 48.13; H, 4.25;N, 10.53 found C, 48.11; H, 4.23; N, 10.64. FAB mass spectrum.m/z=503.25 (M+H)

3-(2-{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-(ethynyl)-propionicacid ethyl ester (17-12) ##STR68## Following the procedures describedfor Scheme 16, the acid 17-7 was coupled with3-amino-3(S)-(ethynl)-propionic acid ethyl ester 2-9 (Zablokie et al, J.Med. Chem., 1995, 38, 2378) to afford the title compound 17-12.

Analysis calculated for C₂₆ H₃₁ N₅ O₄.0.35H₂ O C, 64.53; H, 6.60; N,14.47 found C, 64.52; H, 6.71; N, 14.54. FAB mass spectrum. m/z=478.35(M+H)

3-(2-{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]2H-pyridin-1-yl}-acetylamino)-3(S)-(ethynl)-propionicacid (17-13) ##STR69## Following the procedure described for thepreparation of 16-8, the ester 17-12 was hydrolysed to give the titlecompound 17-13. FAB mass spectrum. m/z=450.23 (M+H) ##STR70##Benzyl-N-(1-cyanoethyl)glycine hydrochloride (18-2) ##STR71## TMSCN(18.8 mL, 141 mmol) was added cautiously to a stirred solution ofbenzylglycine free base (23.3 g 141 mmol--from the HCl salt by partitionbetween EtOAc and brine basified with saturated Na₂ CO₃ solution) andacetaldehyde (7.88 mL, 141 mmol) in CH₂ Cl₂ (50 mL). After 4 h thevolatiles were removed in vacuo and the residue was taken up in EtOAcand washed with brine, dried (Na₂ SO₄) and evaporated in vacuo to anoil. The oil was redissolved in EtOAc and 9.9 M HCl in EtOH (15.25 mL,151 mmol) was added to give a crystalline precipitate which was isolatedby filtration, washing with EtOAc and Et₂ O to give the title compound(18-2):

¹ H NMR (CD₃ OD) δ 1.70 (d, 3H), 4.16 (d, 1H), 4.21 (d, 1H), 4.64 (q,1H), 5.31 (s, 2H), 7.35-7.44 (m, 5H).

1-Benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (18-3)##STR72## A stirred mixture of oxalyl chloride (40.4 mL, 463 mmol) and18-2 (29.51 g, 116 mmol) in 1,2-dichlorobenzene (110 mL) was heated to100° C. for 15 h. The volatiles were removed in vacuo and the residuewas purified by chromatography (silica gel; hexanes followed by 30%EtOAc in hexanes) to give a solid which was heated in EtOAC/hexanes 2:5(140 mL), cooled and collected by filtration to give the title compound18-3 as a pale green solid:

¹ H NMR (CDC1₃) δ 2.35 (s, 3H), 4.88 (s, 2H), 5.24 (s, 2H), 7.38 (m,5H).

3-(4-Methoxybenzylamino)-5-chloro-6-methyl-1-benzyloxycarbonylmethyl-pyrazinone (18-4) ##STR73## A solution of the pyrazinone 18-3 (5 g,15.3 mmol) and 4 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL)was heated at 80° C. for 2 h. The solution was cooled and filtered. Thefiltrate was concentrated in vacuo, the residue swished with MeOH andfiltered to afford the title compound as a solid:

¹ H NMR (CDCl₃) δ 2.23 (s, 3H), 3.82 (s, 3H), 4.5 (d, 2H), 4.81 (s, 2H),5.22 (s, 2H), 6.25 (t, 1H), 6.85 (m, 2H), 7.27 (m, 2H), 7.38 (m, 5H).

3-(4-Methoxybenzylamino)-5-chloro-6-methyl-1-carboxymethyl pyrazinone(18-5) ##STR74## A solution of the benzyl ester 18-4 (1.06 g, 2.48 mmol)in toluene (60 mL) was degassed with argon and then 150 mg 10% palladiumon carbon was added. The mixture was stirred under an atmosphere ofhydrogen gas for 16 h. The solution was filtered through celite and thesolvent evaporated to give the title compound 18-5 as a white solid:

¹ H NMR (CD₃ OD) δ 2.25 (s, 3H), 3.78 (s, 3H), 4.45 (s, 2H), 4.81 (s,2H), 4.90 (s, 2H), 6.85 (d, 2H), 7.28 (d, 2H).

3-(4-Methoxybenzylamino)-6-methyl-1-carboxymethyl pyrazinone (18-6)##STR75## The acid 18-5 (810 mg) was dissolved in 40 mL 1 N NaOH and 40mL MeOH at room temperature and was treated with Raney nickel suspension(˜5 g). A second charge of Raney nickel (˜5 g) and 1 N NaOH (20 mL) wasadded after 3 h. After 6 h, the suspension was filtered through celitewashing with water and MeOH. The volatiles were removed in vacuo and theresidue then taken up 1 N HCl (˜5 mL). Saturated NaHCO₃ solution wasadded until pH˜7-8 and the solution was extracted exhaustively withEtOAc/THF. After drying (MgSO₄), the solvent was removed to give thetitle compound 18-6 as a solid which was used as such:

¹ H NMR (CD₃ OD) δ 2.16 (s, 3H), 3.76 (s, 3H), 4.46 (s, 2H), 4.64 (s,2H), 4.86 (s, 2H), 6.65 (s, 1H), 6.85 (d, 2H), 7.25 (d, 2H).

3-Amino-6-methyl-1-carboxymethylpyrazinone (18-7) ##STR76## Thepyrazinone 18-6 (900 mg) was heated at reflux in trifluoroacetic acid(20 mL) for 7 h. The volatiles were removed in vacuo and the residue wasazeotroped with CH₂ Cl₂, then EtOAc then MeOH. MeOH was added to theresidue and the solution filtered to remove impurities. Removal of themethanol then afforded the title compound 18-7 which was used as such:

¹ H NMR (CD₃ OD) δ 2.22 (s, 3H), 4.82 (s, 2H), 6.58 (s, 1H).

3-(3-Fluorophenyl)-3-(2-{6-methyl-2-oxo-3-amino]2H-pyrazin-1-yl}-acetylamino)propionicacid ethyl ester (18-8) ##STR77## Following the procedure described forthe preparation of 16-6, the acid 18-7 was coupled with the amine 17-8to yield the title compound 18-8.

¹ H NMR (CDCl₃) δ 1.15 (t, 3H), 2.23 (s, 3H), 2.78 (dd, 1H), 2.84 (dd,1H), 4.05 (q, 2H), 4.68 (ABq, 2H), 5.30 (br s, 2H), 5.35 (m, 1H), 6.68(s, 1H), 6.9-7.1 (m, 3H), 7.27 (m, 1H), 7.57 (d, 2H).

3-(3-Fluorophenyl)-3-(2-{6-methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyrazin-1-yl}-acetylamino)propionicacid ditrifluoroacetate (18-9) ##STR78## Following the proceduredescribed for the synthesis of 16-9, the amine 18-8 was coupled with14-3 and the product hydrolyzed to yield the title compound 18-9.

Analysis calculated for C₂₅ H₂₇ N₆ O₄ F.2.25TFA.0.85H₂ O C, 46.23; H,4.07; N, 10.97 found C, 46.22; H, 4.00; N, 11.12. FAB mass spectrum.m/z=495.26 (M+H) ##STR79##

The test procedures employed to measure ανβ3 binding and the boneresorption inhibiting activity of the compounds of the present inventionare described below.

Bone Resorption-Pit Assay

When osteoclasts engage in bone resorption, they will literally causethe formation of pits in the surface of bone that they are acting upon.Therefore, when testing compounds for their ability to inhibitosteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.

Consecutive 200 micron thick cross sections from a six mm cylinder ofbovine femur diaphysis were cut with a low speed diamond saw (Isomet,Beuler, Ltd., Lake Bluff, Ill.). Bone slices were pooled, placed in a10% ethanol solution and refrigerated until further use.

Prior to experimentation, bone slices were ultrasonicated twice, 20minutes each in H₂ O. Cleaned slices were placed in 96 well plates suchthat two control lanes and one lane for each drug dosage are available.Each lane represents either triplicate or quadruplicate cultures. Thebone slices in 96 well plates were sterilized by UV irradiation. Priorto incubation with osteoclasts, the bone slices were hydrated by theaddition of 0.1 ml Medium 199, pH 6.9 containing 15% fetal bovine serumand 1% penicillin/streptomycin.

Osteoclasts were isolated from the long bones of 1 to 3 day old rat pups(Sprague-Dawley) by modifications of Chambers et al., (J. Cell. Science,66:383-399). The resulting suspension (0.75 ml/bone) was gentlytriturated 90-120 times using a wide bore transfer pipet. The cellularpopulation was separated from bone fragments by a cell strainer with a100 micron nylon mesh. 100 μl of the cell suspension was placed ontoeach bone slice. Test compounds were then added at the desiredexperimental concentrations.

Bone slices exposed to osteoclasts for 20-24 hrs were processed forstaining. Tissue culture media was removed from each bone slice. Eachwell was washed with 200 μl of H₂ O, and the bone slices were then fixedfor 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.4. Afterfixation, any remaining cellular debris was removed by 2 min.ultrasonication in the presence of 0.25 M NH₄ OH followed by 2×15 minultrasonication in H₂ O. The bone slices were immediately stained for6-8 min with filtered 1% toluidine blue and 1% borax.

After the bone slices have dried, resorption pits were counted in testand control slices. Resorption pits were viewed in a Microphot Fx(Nikon) fluorescence microscope using a polarizing Nikon IGS filtercube. Test dosage results were compared with controls and resulting IC₅₀values were determined for each compound tested.

The appropriateness of extrapolating data from this assay to utility anduse in mammalian (including human) disease states is supported by theteaching found in Sato, M., et al., Journal of Bone and MineralResearch, Vol. 5, No. 1, 1990. That article teaches that certainbisphosphonates have been used clinically and appear to be effective inthe treatment of Paget's disease, hypercalcemia of malignancy,osteolytic lesions produced by bone metastases, and bone loss due toimmobilization or sex hormone deficiency. These same bisphosphonates arethen tested in the resorption pit assay described above to confirm acorrelation between their known utility and positive performance in theassay.

EIB Assay

Duong et al., J. Bone Miner. Res., 8:S 378, describe a system forexpressing the human integrin αvβ3. It has been suggested that theintegrin stimulates attachment of osteoclasts to bone matrix, sinceantibodies against the integrin, or RGD-containing molecules, such asechistatin (European Publication 382 451), can effectively block boneresorption.

Reaction Mixture:

1. 175 μl TBS buffer (50 mM Tris·HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mMCaCl₂, 1 mM MgCl₂).

2. 25 μl cell extract (dilute with 100 mM octylglucoside buffer to give2000 cpm/25 μl).

3. ¹²⁵ I-echistatin (25 μl/50,000 cpm) (see EP 382 451).

4. 25 μl buffer (total binding) or unlabeled echistatin (non-specificbinding).

The reaction mixture was then incubated for 1 h at room temp. Theunbound and the bound αvβ3 were separated by filtration using a SkatronCell Harvester. The filters (prewet in 1.5% poly-ethyleneimine for 10mins) were then washed with the wash buffer (50 mM Tris HCl, 1 mM CaCl₂/MgCl₂, pH 7.2). The filter was then counted in a gamma counter.

SPA Assay

Materials:

1. Wheatgerm agglutinin Scintillation Proximity Beads (SPA): Amersham

2. Octylglucopyranoside: Calbiochem

3. HEPES: Calbiochem

4. NaCl: Fisher

5. CaCl₂ : Fisher

6. MgCl₂ : SIGMA

7. Phenylmethylsulfonylfluoride (PMSF): SIGMA

8. Optiplate: PACKARD

9. Compound 8-10 (specific activity 500-1000 Ci/mmole)

10. test compound

11. Purified integrin receptor: α.sub.ν β3 was purified from 293 cellsoverexpressing α.sub.ν β3 (Duong et al., J. Bone Min. Res., 8:S378,1993) according to Pytela (Methods in Enzymology, 144:475, 1987)

12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca²⁺ /Mg²⁺,0.5 mM PMSF

13. 50 mM octylglucoside in binding buffer: 50-OG buffer

Procedure

1. Pretreatment of SPA beads:

500 mg of lyophilized SPA beads were first washed four times with 200 mlof 50-OG buffer and once with 100 ml of binding buffer, and thenresuspended in 12.5 ml of binding buffer.

2. Preparation of SPA beads and receptor mixture

In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads were suspendedin 97.5 μl of binding buffer and 20 μl of 50-OG buffer. 5 μl (˜30 ng/μl)of purified receptor was added to the beads in suspension with stirringat room temperature for 30 minutes. The mixture was then centrifuged at2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4° C.The pellets were then resuspended in 50 μl of binding buffer and 25 μlof 50-OG buffer.

3. Reaction

The following were sequentially added into Optiplate in correspondingwells:

(i) Receptor/beads mixture (75 μl)

(ii) 25 μl of each of the following: compound to be tested, bindingbuffer for total binding or 8-8 for non-specific binding (finalconcentration 1 μM)

(iii) 8-10 in binding buffer (25 μl, final concentration 40 μM)

(iv) Binding buffer (125 μl)

(v) Each plate was sealed with plate sealer from PACKARD and incubatedovernight with rocking at 4° C.

4. Plates were counted using PACKARD TOPCOUNT

5. % inhibition was calculated as follows:

A=total counts

B=nonspecific counts

C=sample counts

% inhibition=[{(A-B)-(C-B)}/(A-B)]/(A-B)×100

Ocform Assay

Osteoblast-like cells (1.8 cells), originally derived from mousecalvaria, were plated in CORNING 24 well tissue culture plates in α MEMmedium containing ribo- and deoxyribonucleosides, 10% fetal bovine serumand penicillin-streptomycin. Cells were seeded at 40,000/well in themorning. In the afternoon, bone marrow cells were prepared from six weekold male Balb/C mice as follows:

Mice were sacrificed, tibiae removed and placed in the above medium. Theends were cut off and the marrow was flushed out of the cavity into atube with a 1 mL syringe with a 27.5 gauge needle. The marrow wassuspended by pipetting up and down. The suspension was passedthrough >100 μm nylon cell strainer. The resulting suspension wascentrifuged at 350×g for seven minutes. The pellet was resuspended, anda sample was diluted in 2% acetic acid to lyse the red cells. Theremaining cells were counted in a hemacytometer. The cells were pelletedand resuspended at 1×10⁶ cells/mL. 50 μL was added to each well of 1.8cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin D₃ (D₃) wasadded to each well to a final concentration of 10 nM. The cultures wereincubated at 37° C. in a humidified, 5% CO₂ atmosphere. After 48 h, themedium was changed. 72 h after the addition of bone marrow, testcompounds were added with fresh medium containing D₃ to quadruplicatewells. Compounds were added again after 48 h with fresh mediumcontaining D₃. After an additional 48 h the medium was removed, cellswere fixed with 10% formaldehyde in phosphate buffered saline for 10minutes at room temperature, followed by a 1-2 minute treatment withethanol:acetone (1:1) and air dried. The cells were then stained fortartrate resistant acid phosphatase as follows:

The cells were stained for 10-15 minutes at room temperature with 50 mMacetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL FastRed Violet LB Salt and 0.1 mg/mL Naphthol AS-MX phosphate. Afterstaining, the plates were washed extensively with deionized water andair dried. The number of multinucleated, positive staining cells werecounted in each well.

αvβ5 Attachment Assay

Duong et al., J. Bone Miner. Res., 11:S 290, describe a system forexpressing the human αvμ5.

Materials:

1. Media and solutions used in this assay are purchased from BRL/Gibco,except BSA and the chemicals are from Sigma.

2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid freeBSA and 2 mM CaCl₂.

3. Glucosaminidase substrate solution: 3.75 mMp-nitrophenyl-N-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25%Triton, pH 5.0.

4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods:

1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4° C. withhuman vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 9/.6), using100 μl/well. Plates were then washed 2× with DPBS and blocked with 2%BSA in DPBS for 2h at room temperature. After additional washes (2×)with DPBS, plates were used for cell attachment assay.

2. 293 (alpha v beta 5) cells were grown in MEM media in presence of 10%fetal calf serum to 90% confluence. Cells were then lifted from disheswith 1× Trypsin/EDTA and washed 3× with serum free MEM. Cells wereresuspended in attachment medium (3×10⁵ cells/ml).

3. Test compounds were prepared as a series of dilutions at 2×concentrations and added as 50 μl/well. Cell suspension was then addedas 50 ml/well. Plates were incubated at 37° C. with 55 CO₂ for 1 hour toallow attachment.

4. Non-adherent cells were removed by gently washing the plates (3×)with DPBS and then incubated with glucosaminidase substrate solution(100 μl/well), overnight at room temperature in the dark. To quantitatecell numbers, standard curve of glucosaminidase activity was determinedfor each experiment by adding samples of cell suspension directly towells containing the enzyme substrate solution.

5. The next day, the reaction was developed by addition of 185 μl/wellof gylcine/EDTA solution and reading absorbance at 405 nm using aMolecular Devices V-Max plate reader. Average test absorbance values (4wells per test samples) were calculated. Then, the number of attachedcells at each drug concentration was quantitated versus the standardcurve of cells using the Softmax program.

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral composition, 100 mg of compound 3-13is formulated with sufficient fmely divided lactose to provide a totalamount of 580 to 590 mg to fill a size O hard gel capsule.

Representative compounds of the present invention were tested and foundto bind to human αvμ3 integrin. These compounds were found to have IC₅₀values in the range of 0.1 to 100 nM in the SPA assay.

Representative compounds of the present invention were tested and foundto inhibit ≧50% the attachment of αvβ5 expressing cells to plates coatedwith vitronectin at concentrations of 1 μM.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of the formula ##STR80## wherein X is selected from a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R¹ and R² ;Y is selected from --(CH₂)_(r) -- or --(CH₂)_(m) --NR³ --(CH₂)_(t) --; Z is selected from ##STR81## R¹, R² and R⁴ are each independently selected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(q) amino, (C₁₋₆ alkyl)_(q) amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q), (C₁₋₈ alkyl)_(q) aminocarbonyl, C₁₋₈ alkyloxycarbonyl amino, (C₁₋₈ alkyl)_(q) aminocarbonyloxy, oxo, (aryl C₁₋₈ alklyl)_(q) amino, (aryl)_(q) amino, aryl C₁₋₈ alkylsulfonylamino, or C₁₋₈ alkylsulfonylamino; R³ is selected fromhydrogen, aryl-(CH₂)_(p) --, C₁₋₅ alkoxycarbonyl, C₃₋₈ cycloalkyl, (aryl)_(q) aminocarbonyl, (aryl C₁₋₅ alkyl)_(q) aminocarbonyl, C₁₋₈ alkyl, aryl C₁₋₆ alkyl, C₁₋₈ alkylsulfonyl, arylsulfonyl, aryl C₁₋₆ alkylsulfonyl, C₁₋₈ alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈ alkoxycarbonyl, C₁₋₈ alkylcarbonyl, arylcarbonyl, aryl C₁₋₆ alkylcarbonyl, or (C₁₋₈ alkyl)_(q) aminocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R¹ and R² ; R⁸ is selected fromhydrogen, aryl, aryl-(CH₂)_(p) --, HC.tbd.C--(CH₂)_(s) --, C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --, aryl-C.tbd.C--(CH₂)_(s) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --, CH₂ ═CH--(CH₂)_(s) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --, C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --, aryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --, or C₁₋₆ alklyaryl-SO₂ --(CH₂)_(s) --; and R¹² is selected fromhydrogen, C₁₋₈ alkyl, aryl, aryl C₁₋₈ alkyl, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, C₁₋₈ alkylaminocarbonylmethylene, or C₁₋₈ dialkylaminocarbonylmethylene; m, s and t are, each independently an integer from 0 to 3; p is an integer from 0 to 4; q is an integer from 0to 2; r is an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 wherein X is selected from ##STR82## R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, or aryl C₁₋₈ alkyl; and R⁸ is selected fromhydrogen, ##STR83## indolyl-(CH₂)_(p) --, HC.tbd.C--(CH₂)_(s) --, C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --, aryl-C.tbd.C--(CH₂)_(s) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --, CH₂ ═CH--(CH₂)_(s) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --, C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --, aryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --, or C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; s and r are each independently an integer from 0 to 3; p is an integer from 1 to 2; and the pharmaceutically acceptable salts thereof.
 3. The compound of claim 2 of the formula ##STR84## wherein R⁸ is selected from ##STR85## and indolyl-(CH₂)_(p) --; and R¹² is selected from hydrogen or C₁₋₈ alkyl;and the pharmaceutically acceptable salts thereof.
 4. The compound of claim 3 selected from2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; Ethyl 2-ox o-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine; Ethyl 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; Ethyl 3-(2-{² -oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine ethyl ester; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid ethyl ester; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid; 3-{2-(2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl)-acetylamino}-3(S)-quinolin-3-yl-propionic acid; 3-(2-(5(S)-Ethyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrolidin-1-yl)-acetylamino)-3-(S)-quinolin-3-yl-propionic acid trifluoroacetate; 3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionic acid bis trifluoroacetate; or 3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]napthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionic acid ethyl ester; and the pharmaceutically acceptable salts thereof.
 5. The compound of claim 4, selected from2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine; p1 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; 3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; or 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; or 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof.
 6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 7. A pharmaceutical composition made by combining a compound of claim 1 and a pharmaceutically acceptable carrier.
 8. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. A method of eliciting a vitronectin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of claim
 6. 10. A method of eliciting a vitronectin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula ##STR86## wherein X is selected from a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R¹ and R² ;Y is selected from --(CH₂)_(r) -- or --(CH₂)_(m) --NR³ --(CH₂)_(t) --; Z is selected from ##STR87## R¹, R² and R⁴ are each independently selected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(q) amino, (C₁₋₆ alkyl)_(q) amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(q), (C₁₋₈ alkyl)_(q) aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(q) aminocarbonyloxy, oxo, (aryl C₁₋₈ alkyl)_(q) amino, (aryl)_(q) amino, aryl C₁₋₈ alkylsulfonylamino, or C₁₋₈ alkylsulfonylamino; R³ is selected fromhydrogen, aryl-(CH₂)_(p) --, C₁₋₅ alkoxycarbonyl, C₃₋₈ cycloalkyl, (aryl)_(q) aminocarbonyl, (aryl C₁₋₅ alkyl)_(q) aminocarbonyl, C₁₋₈ alkyl, ayl C₁₋₆ alkyl, C₁₋₈ alkylsulfonyl, arylsulfonyl, aryl C₁₋₆ alkylsulfonyl, C₁₋₈ alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈ alkoxycarbonyl, C₁₋₈ alkylcarbonyl, arylcarbonyl, aryl C₁₋₆ alkylcarbonyl, or (C₁₋₈ alkyl)_(q) aminocarbonyl, wherein any of the alkyl groups may be unsubstituted or substituted with R¹ and R² ; R⁸ is selected fromhydrogen, aryl-(CH₂)_(p) --, HC.tbd.C--(CH₂)_(s) --, C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --, ayl-C.tbd.C--(CH₂)_(s) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --, CH₂ ═CH--(CH₂)_(s) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --, C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --, ary-CH═CH--(CH₂)_(s) --, C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --, or C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; and R¹² is selected fromhydrogen, C₁₋₈ alky, aryl, aryl C₁₋₈ alkyl, C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, C₁₋₈ alkylaminocarbonylmethylene, or C₁₋₈ dialkylaminocarbonylmethylene; m, s and t are each independently an integer from 0 to 3; p is an integer from 0 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and the phamaceutically acceptable salts thereof.
 11. The method of claim 10 wherein X is selected from ##STR88## R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, or aryl C₁₋₈ alkyl; and R⁸ is selected fromhydrogen, ##STR89## indolyl-(CH₂)_(p) --, HC.tbd.C--(CH₂)_(s) --, C₁₋₆ alkyl-C.tbd.C--(CH₂)_(s) --, C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(s) --, aryl-C.tbd.C--(CH₂)_(s) --, C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(s) --, CH₂ ═CH--(CH₂)_(s) --, C₁₋₆ alkyl-CH═CH--(CH₂)_(s) --, C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(s) --, aryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkylaryl-CH═CH--(CH₂)_(s) --, C₁₋₆ alkyl-SO₂ --(CH₂)_(s) --, or C₁₋₆ alkylaryl-SO₂ --(CH₂)_(s) --; s and r are each independently an integer from 0 to 3; p is an integer from 1 to 2; and the pharmaceutically acceptable salts thereof.
 12. The method of claim 11 wherein the compound has the formula ##STR90## wherein R⁸ is selected from ##STR91## and indolyl-(CH₂)_(p) --; and R¹² is selected from hydrogen or C₁₋₈ alkyl;and the pharmaceutically acceptable salts thereof.
 13. The method of claim 12, wherein the compound is selected from2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; Ethyl 2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine; Ethyl 2-oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; Ethyl 3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-(2-{2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine ethyl ester; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine ethyl ester; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2- {2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid ethyl ester; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid; 3-{2-(2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl)-acetylamino}-3(S)-quinolin-3-yl-propionic acid; 3-(2-(5(S)-Ethyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrolidin-1-yl)-acetylamino)-3-(S)-quinolin-3-yl-propionic acid trifluoroacetate; 3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionic acid bis trifluoroacetate; or 3-(2-{6-Methyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]napthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionic acid ethyl ester; and the pharmaceutically acceptable salts thereof.
 14. The method of claim 13, wherein the compound is selected from2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperin-1-yl-acetyl-3(S)-pyridin-3-yl-β-alanine trifluoroacetate; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-imidazolidin-1-yl-acetyl-3-(S)-pyridin-3-yl-β-alanine; 2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(R)-(2-ethylindol-3-yl)-β-alanine; 3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 3-{2-[6-Oxo-1-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino}-3-(S)-pyridin-3-yl-propionic acid; 2-Oxo-5(R)-methyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-ethynyl-β-alanine; 2-Oxo-5(S)-benzyl-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-yl-β-alanine; 5(R)-Methyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetyl-3(S)-alkynyl-β-alanine; or 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetylamino)-propionic acid; and the pharmaceutically acceptable salts thereof.
 15. The method of claim 10, wherein the vitronectin receptor antagonizing effect is an αvβ3 antagonizing effect.
 16. The method of claim 15 wherein the αvβ3 antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
 17. The method of claim 16, wherein the αvβ3 antagonizing effect is the inhibition of bone resorption. 